U.S. patent application number 16/006381 was filed with the patent office on 2018-12-13 for systems and methods for identifying cancer treatments from normalized biomarker scores.
The applicant listed for this patent is Ravshan Ataullakhanov, Alexander Bagaev, Feliks Frenkel. Invention is credited to Ravshan Ataullakhanov, Alexander Bagaev, Feliks Frenkel.
Application Number | 20180358125 16/006381 |
Document ID | / |
Family ID | 62779138 |
Filed Date | 2018-12-13 |
United States Patent
Application |
20180358125 |
Kind Code |
A1 |
Bagaev; Alexander ; et
al. |
December 13, 2018 |
SYSTEMS AND METHODS FOR IDENTIFYING CANCER TREATMENTS FROM
NORMALIZED BIOMARKER SCORES
Abstract
Techniques for identifying the subject as a member of one or
more cohorts. The techniques include: obtaining sequencing data for
a subject; accessing biomarker information indicating a
distribution of values for each biomarker, across a respective
group of people, in at least a reference subset of the plurality of
biomarkers, each of the plurality of biomarkers being associated
with at least one candidate therapy; determining, using the
sequencing data and the biomarker information, a normalized score
for each biomarker in at least a subject subset of the plurality of
biomarkers to obtain a set of normalized biomarkers for the
subject; identifying the subject as a member of one or more cohorts
based on the set of normalized biomarker scores for the subject,
wherein each of the one or more cohorts is associated with a
positive or negative outcome of the at least one candidate
therapy.
Inventors: |
Bagaev; Alexander; (Moscow,
RU) ; Frenkel; Feliks; (Moscow, RU) ;
Ataullakhanov; Ravshan; (Moscow, RU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bagaev; Alexander
Frenkel; Feliks
Ataullakhanov; Ravshan |
Moscow
Moscow
Moscow |
|
RU
RU
RU |
|
|
Family ID: |
62779138 |
Appl. No.: |
16/006381 |
Filed: |
June 12, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62598440 |
Dec 13, 2017 |
|
|
|
62518787 |
Jun 13, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G16H 50/30 20180101;
C12Q 2600/158 20130101; G16H 70/20 20180101; G16H 50/70 20180101;
G16B 5/20 20190201; G16H 20/10 20180101; G16H 10/20 20180101; G06F
17/18 20130101; G16H 50/20 20180101; G16B 45/00 20190201; G16B
20/00 20190201; G16B 5/00 20190201; G16B 50/00 20190201; G16H 20/40
20180101; Y02A 90/10 20180101; G16B 40/00 20190201; G16H 20/00
20180101; G16H 50/50 20180101; C12Q 1/6886 20130101; G06F 16/285
20190101; C12Q 2600/156 20130101 |
International
Class: |
G16H 50/20 20060101
G16H050/20; G06F 19/28 20060101 G06F019/28; G06F 19/26 20060101
G06F019/26; G16H 10/20 20060101 G16H010/20 |
Claims
1. A system, comprising: at least one computer hardware processor;
at least one database that stores biomarker information; and at
least one non-transitory computer-readable storage medium storing
processor-executable instructions that, when executed by the at
least one computer hardware processor, cause the at least one
computer hardware processor to perform: obtaining sequencing data
about at least one biological sample of a subject; accessing, in
the at least one database, biomarker information indicating a
distribution of values for each biomarker, across a respective
group of people, in at least a reference subset of the plurality of
biomarkers, each of the plurality of biomarkers being associated
with at least one candidate therapy; determining, using the
sequencing data and the biomarker information, a normalized score
for each biomarker in at least a subject subset of the plurality of
biomarkers to obtain a set of normalized biomarkers for the
subject; identifying the subject as a member of one or more cohorts
based on the set of normalized biomarker scores for the subject,
wherein each of the one or more cohorts is associated with a
positive or negative outcome of the at least one candidate therapy;
and outputting an indication of the one or more cohorts in which
the subject is a member.
2. The system of claim 1, wherein the at least one candidate
therapy is associated with a clinical trial, optionally wherein the
clinical trial is ongoing or the clinical trial is recruiting.
3. The system of claim 1, wherein the positive outcome is an
improvement in one or more aspects of a cancer or in one or more
cancer symptoms.
4. The system of claim 3, wherein the improvement in one or more
aspects of a cancer or one or more cancer symptoms is selected from
the group consisting of: decrease in tumor size, decrease in tumor
number, decrease in number or percentage of cancerous cells in the
body of the subject, and slowing of cancer growth.
5. The system of claim 1, wherein the negative outcome is a cancer
therapy-related adverse effect, an deterioration in one or more
aspects of a cancer, or a deterioration in one or more cancer
symptoms.
6. The system of claim 5, wherein the cancer therapy-related
adverse effect is selected from: cutaneous toxicity,
thrombocytopenia, hepatotoxicity, neurotoxicity, nephrotoxicity,
cardiotoxicity, hemorrhagic cystitis, immune-related toxicity, and
death.
7. The system of claim 5, wherein the deterioration in one or more
aspects of a cancer or one or more cancer symptoms is selected from
the group consisting of: increase in tumor size, increase in tumor
number, increase in number or percentage of cancerous cells in the
body of the subject, no slowing of cancer growth, and death.
8. The system of claim 1, wherein the sequencing data is one or
more of: DNA sequencing data, RNA sequencing data, or proteome
sequencing data.
9. The system of claim 1, wherein the sequencing data is obtained
using one or more of the following techniques: whole genome
sequencing (WGS), whole exome sequencing (WES), whole transcriptome
sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray,
DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP)
genotyping.
10. The system of claim 1, wherein the biological sample is from a
tumor or tissue known or suspected of having cancerous cells.
11. The system of claim 1, wherein each of the at least one
biological samples is a bodily fluid, a cell sample, a liquid
biopsy, or a tissue biopsy.
12. The system of claim 1, wherein the processor-executable
instructions further cause the at least one processor to perform:
generating a graphical user interface (GUI) comprising: a first
portion associated with the at least one candidate therapy, the
first portion including a first plurality of GUI elements, each of
the first plurality of GUI elements being associated with a
respective biomarker in the plurality of biomarkers and having at
least one visual characteristic determined based on a difference
score of the respective biomarker; and displaying the generated
GUI.
13. The system of claim 12, wherein the at least one visual
characteristic comprises color of a GUI element and/or size of the
GUI element.
14. The system of claim 12, wherein the processor-executable
instructions further cause the at least one processor to perform:
in response to receiving, via the GUI, a user selection of the at
least one candidate therapy, presenting, via the GUI, information
about at least one biomarker with which at least one of the first
plurality of GUI elements is associated.
15. At least one non-transitory computer-readable storage medium
storing processor-executable instructions that, when executed by at
least one computer hardware processor, cause the at least one
computer hardware processor to perform: obtaining sequencing data
about at least one biological sample of a subject; accessing, in at
least one database, biomarker information indicating a distribution
of values for each biomarker, across a respective group of people,
in at least a reference subset of the plurality of biomarkers, each
of the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
16. The at least one non-transitory computer-readable storage
medium of claim 15, wherein the at least one candidate therapy is
associated with a clinical trial, optionally wherein the clinical
trial is ongoing or the clinical trial is recruiting.
17. The at least one non-transitory computer-readable storage
medium of claim 15, wherein the positive outcome is an improvement
in one or more aspects of a cancer or in one or more cancer
symptoms.
18. A method comprising: using at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of the plurality of biomarkers, each of
the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
19. The method of claim 18, wherein the at least one candidate
therapy is associated with a clinical trial, optionally wherein the
clinical trial is ongoing or the clinical trial is recruiting.
20. The method of claim 18, wherein the positive outcome is an
improvement in one or more aspects of a cancer or in one or more
cancer symptoms.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of the filing date of U.S. provisional patent application
Ser. No. 62/518,787, entitled "Systems and Methods for Identifying
Cancer Treatments from Sequence Data", filed Jun. 13, 2017 and U.S.
provisional patent application Ser. No. 62/598,440, entitled
"Systems and Methods Identifying Cancer Treatments from Sequence
Data," filed Dec. 13, 2017, the entire contents of each of which
are incorporated herein by reference.
[0002] This application is filed on the same day as International
Application No.: PCT/US18/37017, entitled "SYSTEMS AND METHODS FOR
GENERATING, VISUALIZING AND CLASSIFYING MOLECULAR FUNCTIONAL
PROFILES", bearing Attorney Docket No. B1462.70002WO00;
International Application No.: PCT/US18/37018, entitled "SYSTEMS
AND METHODS FOR IDENTIFYING RESPONDERS AND NON-RESPONDERS TO IMMUNE
CHECKPOINT BLOCKADE THERAPY", bearing Attorney Docket No.
B1462.70003WO00; and International Application No.: PCT/US18/37008,
entitled "SYSTEMS AND METHODS FOR IDENTIFYING CANCER TREATMENTS
FROM NORMALIZED BIOMARKER SCORES", bearing Attorney Docket No.
B1462.70004WO00, the entire contents of each of which are
incorporated herein by reference.
FIELD
[0003] Aspects of the technology described herein relate to
predicting treatment efficacy based on subject (e.g., patient)
specific information such as a subject's (e.g., patient's)
biomarkers.
[0004] Some aspects of the technology described herein relate to
determining therapy scores (for one or more potential treatments)
and determining therapy scores before and after a treatment. Some
aspects of the technology described herein relate to generating a
graphical user interface (GUI) for visualizing therapy scores.
[0005] Some aspects of the technology described herein relate to
determining impact scores (for treatments). Some aspects of the
technology described herein relate to generating a graphical user
interface for visualizing impact scores.
[0006] Some aspects of the technology described herein relate to
determining normalized biomarker scores for a subject. Some aspects
of the technology described herein relate to identifying the
subject as a member of one or more cohorts using normalized
biomarkers scores. Some aspects of the technology described herein
relate to outputting such information (e.g., to one or more users).
Some aspects of the technology described herein relate to potential
inclusion or exclusion of a subject from a clinical trial.
BACKGROUND
[0007] Correctly selecting one or more effective therapies for a
subject (e.g., a patient) with cancer or determining the
effectiveness of a treatment can be crucial for the survival and
overall wellbeing of that subject. Advances in identifying
effective therapies and understanding their effectiveness or
otherwise aiding in personalized care of patients with cancer are
needed.
SUMMARY
[0008] Provided herein, inter alia, are systems and methods for
determining therapy scores for multiple therapies based on
normalized biomarker scores. Such information, in some embodiments,
is output to a user in a graphical user interface (GUI).
[0009] Systems and methods for determining therapy scores for
multiple therapies based on normalized biomarker scores comprises,
in some embodiments, accessing sequence data for a subject,
accessing biomarker information indicating distribution of values
for biomarkers associated with multiple therapies, determining
normalized biomarker scores for the subject using sequencing data
and biomarker information, and determining therapy scores for the
multiple therapies based on normalized biomarker scores.
[0010] Provided herein, inter alia, are systems and methods for
determining impact score for a candidate therapy using first and
second normalized biomarker scores. Such information, in some
embodiments, is output to a user in a graphical user interface
(GUI).
[0011] Systems and methods for determining impact score for a
candidate therapy using first and second normalized biomarker
scores comprises, in some embodiments, obtaining first sequencing
data for a subject prior to administration of candidate therapy,
obtaining second sequencing data for a subject subsequent to
administration of candidate therapy, accessing biomarker
information indicating distribution of values for a biomarker
associated with the candidate therapy, determining first and second
biomarker scores for the subject using first sequencing data,
second sequencing data, and biomarker information, and determining
impact score for the candidate therapy using first and second
normalized biomarker scores.
[0012] Provided herein, inter alia, are systems and methods for
determining therapy scores for at least two selected therapies
based on normalized biomarker scores for the at least three
biomarkers. Such information, in some embodiments, is output to a
user in a graphical user interface (GUI).
[0013] Systems and methods for determining therapy scores for at
least two selected therapies based on normalized biomarker scores
for the at least three biomarkers comprises, in some embodiments,
obtaining sequencing data for a subject, accessing biomarker
information for at least three biomarkers associated with at least
two selected therapies, determining first and second sets of
normalized biomarker scores for the subject using sequencing data
and biomarker information, and determining therapy scores for the
at least two selected therapies based on normalized biomarker
scores for the at least three biomarkers.
[0014] Provided herein, inter alia, are systems and methods for
obtaining first and second therapy scores for first and second
therapies. Such information, in some embodiments, is output to a
user in a graphical user interface (GUI).
[0015] Systems and methods for obtaining first and second therapy
scores for first and second therapies comprises, in some
embodiments, obtaining sequence data for a subject, accessing
biomarker information indicating distribution of values for
biomarkers associated with multiple therapies, determining first
and second sets of normalized biomarker scores for the subject
using sequencing data and biomarker information, and obtaining
first and second therapy scores for first and second therapies.
[0016] Provided herein, inter alia, are systems and methods for
identifying a subject as a member of a cohort using normalized
biomarker scores. Such information, in some embodiments, is output
to a user in a graphical user interface (GUI).
[0017] Systems and methods for identifying a subject as a member of
a cohort using normalized biomarker scores comprises, in some
embodiments, obtaining sequencing data for a subject, accessing
biomarker information indicating distribution of values for
biomarkers associated with multiple therapies, determining
normalized biomarker scores for the subject using sequencing data
and biomarker information, and identifying the subject as a member
of a cohort using normalized biomarker scores.
[0018] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information, a normalized score for each
biomarker in at least a subject subset of the plurality of
biomarkers to obtain a set of normalized biomarker scores for the
subject, wherein the subject subset of the plurality of biomarkers
is a subset of the reference subset of the plurality of biomarkers;
and determining, using the set of normalized biomarker scores for
the subject, therapy scores for the plurality of therapies, each of
the therapy scores indicative of predicted response of the subject
to administration of a respective therapy in the plurality of
therapies.
[0019] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker
in at least a reference subset of a plurality of biomarkers across
a respective group of people, each of the plurality of biomarkers
being associated with at least one therapy in a plurality of
therapies; determining, using the sequencing data and the biomarker
information, a normalized score for each biomarker in at least a
subject subset of the plurality of biomarkers to obtain a set of
normalized biomarker scores for the subject, wherein the subject
subset of the plurality of biomarkers is a subset of the reference
subset of the plurality of biomarkers; and determining, using the
set of normalized biomarker scores for the subject, therapy scores
for the plurality of therapies, each of the therapy scores
indicative of predicted response of the subject to administration
of a respective therapy in the plurality of therapies.
[0020] In one aspect provided herein is a method, comprising using
at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker in at least
a reference subset of a plurality of biomarkers across a respective
group of people, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information, a normalized score for each biomarker in at least a
subject subset of the plurality of biomarkers to obtain a set of
normalized biomarker scores for the subject, wherein the subject
subset of the plurality of biomarkers is a subset of the reference
subset of the plurality of biomarkers; and determining, using the
set of normalized biomarker scores for the subject, therapy scores
for the plurality of therapies, each of the therapy scores
indicative of predicted response of the subject to administration
of a respective therapy in the plurality of therapies.
[0021] In one aspect provided herein is a system comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining first sequencing data about at
least one biological sample of a subject prior to administration of
a candidate therapy; obtaining second sequencing data about at
least one other biological sample of the subject subsequent to
administration of the candidate therapy; accessing, in the at least
one database, biomarker information indicating a distribution of
values for each biomarker, across a respective group of people, in
at least a reference subset of a plurality of biomarkers;
determining, using the first and second sequencing data and the
biomarker information, a first set of normalized biomarker scores
for the subject and a second set of normalized biomarker scores for
the subject; and determining, using the first and second sets of
normalized biomarker scores for the subject, an impact score for
the candidate therapy, wherein the impact score is indicative of
response of the subject to administration of the candidate
therapy.
[0022] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining first sequencing data about at least one
biological sample of a subject prior to administration of a
candidate therapy; obtaining second sequencing data about at least
one other biological sample of the subject subsequent to
administration of the candidate therapy; accessing, in at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of a plurality of biomarkers; determining,
using the first and second sequencing data and the biomarker
information, a first set of normalized biomarker scores for the
subject and a second set of normalized biomarker scores for the
subject; and determining, using the first and second sets of
normalized biomarker scores for the subject, an impact score for
the candidate therapy, wherein the impact score is indicative of
response of the subject to administration of the candidate
therapy.
[0023] In one aspect provided herein is a method, comprising: using
at least one computer hardware processor to perform: obtaining
first sequencing data about at least one biological sample of a
subject prior to administration of a candidate therapy; obtaining
second sequencing data about at least one other biological sample
of the subject subsequent to administration of the candidate
therapy; accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker, across a
respective group of people, in at least a reference subset of a
plurality of biomarkers; determining, using the first and second
sequencing data and the biomarker information, a first set of
normalized biomarker scores for the subject and a second set of
normalized biomarker scores for the subject; and determining, using
the first and second sets of normalized biomarker scores for the
subject, an impact score for the candidate therapy, wherein the
impact score is indicative of response of the subject to
administration of the candidate therapy.
[0024] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information: a first set of normalized scores for
a first set of biomarkers associated with a first therapy in the
plurality of therapies; and a second set of normalized scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized scores as input to a statistical model to obtain
a first therapy score for the first therapy; providing the second
set of normalized scores as input to the statistical model to
obtain a second therapy score for the second therapy; generating a
graphical user interface (GUI), wherein the GUI comprises: a first
portion associated with a first therapy in the plurality of
therapies, the first portion including a first plurality of GUI
elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a normalized score of the respective biomarker in the
first set of normalized scores; and a second portion associated
with a second therapy in the plurality of therapies, the second
portion including a second plurality of GUI elements different from
the first plurality of GUI elements, each of the second plurality
of GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the second set of normalized scores; and
displaying the generated GUI.
[0025] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information: a first set of normalized scores for
a first set of biomarkers associated with a first therapy in the
plurality of therapies; and a second set of normalized scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized scores as input to a statistical model to obtain
a first therapy score for the first therapy; providing the second
set of normalized scores as input to the statistical model to
obtain a second therapy score for the second therapy; generating a
graphical user interface (GUI), wherein the GUI comprises: a first
portion associated with a first therapy in the plurality of
therapies, the first portion including a first plurality of GUI
elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a normalized score of the respective biomarker in the
first set of normalized scores; and a second portion associated
with a second therapy in the plurality of therapies, the second
portion including a second plurality of GUI elements different from
the first plurality of GUI elements, each of the second plurality
of GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the second set of normalized scores; and
displaying the generated GUI.
[0026] In one aspect provided herein is a method, comprising using
the at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker in at least
a reference subset of a plurality of biomarkers across a respective
group of people, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information: a first set of normalized scores for a first set of
biomarkers associated with a first therapy in the plurality of
therapies; and a second set of normalized scores for a second set
of biomarkers associated with a second therapy in the plurality of
therapies, wherein the first set of biomarkers is different from
the second set of biomarkers; providing the first set of normalized
scores as input to a statistical model to obtain a first therapy
score for the first therapy; providing the second set of normalized
scores as input to the statistical model to obtain a second therapy
score for the second therapy; generating a graphical user interface
(GUI), wherein the GUI comprises: a first portion associated with a
first therapy in the plurality of therapies, the first portion
including a first plurality of GUI elements, each of the first
plurality of GUI elements being associated with a respective
biomarker in the plurality of biomarkers and having at least one
visual characteristic determined based on a normalized score of the
respective biomarker in the first set of normalized scores; and a
second portion associated with a second therapy in the plurality of
therapies, the second portion including a second plurality of GUI
elements different from the first plurality of GUI elements, each
of the second plurality of GUI elements being associated with a
respective biomarker in the plurality of biomarkers and having at
least one visual characteristic determined based on a normalized
score of the respective biomarker in the second set of normalized
scores; and displaying the generated GUI.
[0027] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of the plurality of biomarkers, each of
the plurality of biomarkers being associated with at least one
therapy in a plurality of therapies; determining, using the
sequencing data and the biomarker information: a first set of
normalized biomarker scores for a first set of biomarkers
associated with a first therapy in the plurality of therapies; and
a second set of normalized biomarker scores for a second set of
biomarkers associated with a second therapy in the plurality of
therapies, wherein the first set of biomarkers is different from
the second set of biomarkers; providing the first set of normalized
biomarker scores as input to a statistical model to obtain a first
therapy score for the first therapy; providing the second set of
normalized biomarker scores as input to the statistical model to
obtain a second therapy score for the second therapy; wherein the
plurality of therapies comprise at least two therapies selected
from the group consisting of: an anti-PD1 therapy, an anti-CTLA4
therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer
vaccine therapy, an anti-angiogenic therapy, and an anti-CD20
therapy, and wherein the plurality of biomarkers associated with
each of the plurality of therapies comprises at least three
biomarkers selected from the group of biomarkers associated with
the respective therapy in Table 2.
[0028] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker,
across a respective group of people, in at least a reference subset
of the plurality of biomarkers, each of the plurality of biomarkers
being associated with at least one therapy in a plurality of
therapies; determining, using the sequencing data and the biomarker
information: a first set of normalized biomarker scores for a first
set of biomarkers associated with a first therapy in the plurality
of therapies; and a second set of normalized biomarker scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized biomarker scores as input to a statistical model
to obtain a first therapy score for the first therapy; providing
the second set of normalized biomarker scores as input to the
statistical model to obtain a second therapy score for the second
therapy; wherein the plurality of therapies comprise at least two
therapies selected from the group consisting of: an anti-PD1
therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha
therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy, and wherein the plurality of
biomarkers associated with each of the plurality of therapies
comprises at least three biomarkers selected from the group of
biomarkers associated with the respective therapy in Table 2.
[0029] In one aspect provided herein is a method, comprising using
at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker, across a
respective group of people, in at least a reference subset of the
plurality of biomarkers, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information: a first set of normalized biomarker scores for a first
set of biomarkers associated with a first therapy in the plurality
of therapies; and a second set of normalized biomarker scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized biomarker scores as input to a statistical model
to obtain a first therapy score for the first therapy; providing
the second set of normalized biomarker scores as input to the
statistical model to obtain a second therapy score for the second
therapy; wherein the plurality of therapies comprise at least two
therapies selected from the group consisting of: an anti-PD1
therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha
therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy, and wherein the plurality of
biomarkers associated with each of the plurality of therapies
comprises at least three biomarkers selected from the group of
biomarkers associated with the respective therapy in Table 2.
[0030] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of the plurality of biomarkers, each of
the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
[0031] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker,
across a respective group of people, in at least a reference subset
of the plurality of biomarkers, each of the plurality of biomarkers
being associated with at least one candidate therapy; determining,
using the sequencing data and the biomarker information, a
normalized score for each biomarker in at least a subject subset of
the plurality of biomarkers to obtain a set of normalized
biomarkers for the subject; identifying the subject as a member of
one or more cohorts based on the set of normalized biomarker scores
for the subject, wherein each of the one or more cohorts is
associated with a positive or negative outcome of the at least one
candidate therapy; and outputting an indication of the one or more
cohorts in which the subject is a member.
[0032] In one aspect a method comprising using at least one
computer hardware processor to perform: obtaining sequencing data
about at least one biological sample of a subject; accessing, in at
least one database, biomarker information indicating a distribution
of values for each biomarker, across a respective group of people,
in at least a reference subset of the plurality of biomarkers, each
of the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Various aspects and embodiments will be described with
reference to the following figures. The figures are not necessarily
drawn to scale.
[0034] FIG. 1A is a diagram of an illustrative process for
obtaining patient data and providing that data to a doctor, in
accordance with some embodiments of the technology described
herein.
[0035] FIG. 1B is a block diagram of patient data that may be
presented to a user, in accordance with some embodiments of the
technology described herein.
[0036] FIG. 1C is a graphical representation of patient data that
may be presented to a user, in accordance with some embodiments of
the technology described herein.
[0037] FIG. 2A is a flow chart of an illustrative process for
determining therapy scores for multiple therapies based normalized
biomarker scores, in accordance with some embodiments of the
technology described herein.
[0038] FIG. 2B is a flow chart of an illustrative process for
determining impact score for a candidate therapy using a first
normalized biomarker score and a second normalized biomarker score,
in accordance with some embodiments of the technology described
herein.
[0039] FIG. 2C is a flow chart of an illustrative process for
determining therapy scores for that at least two selected therapies
based on normalized biomarker scores for the at least three
biomarkers, in accordance with some embodiments of the technology
described herein.
[0040] FIG. 2D is a flow chart of an illustrative process for
obtaining first and second therapy scores for first and second
therapies, in accordance with some embodiments of the technology
described herein.
[0041] FIG. 2E is a flow chart of an illustrative process for
identifying a subject as a member of a cohort using normalized
biomarker scores, in accordance with some embodiments of the
technology described herein.
[0042] FIG. 3 is a graphical representation of biomarker value
distribution for a large patient cohort, as determined in
accordance with some embodiments of the technology described
herein.
[0043] FIG. 4 is a graphical representation of patient therapy
scores calculated as the sum of positive and negative biomarkers,
in accordance with some embodiments of the technology described
herein.
[0044] FIG. 5 is a graphical representation of patient therapy
scores calculated for multiple therapies for a patient that has
been determined as responsive (Patient 1) or non-responsive
(Patient 2) to an anti-PD1 therapy (Pembrolizumab), in accordance
with some embodiments of the technology described herein.
[0045] FIG. 6A is a screenshot presenting normalized biomarker
values calculated for different immunotherapies, in accordance with
some embodiments of the technology described herein.
[0046] FIG. 6B is a screenshot presenting patient therapy scores
for different immunotherapies calculated using normalized biomarker
values, in accordance with some embodiments of the technology
described herein.
[0047] FIG. 6C is a screenshot presenting information related to
biomarkers used to calculate patient therapy scores, in accordance
with some embodiments of the technology described herein.
[0048] FIG. 7A is a graphical representation of therapy scores
calculated for patients treated with an anti-PD1 therapy
(Pembrolizumab), in accordance with some embodiments of the
technology described herein. Patients with progressive disease (PD)
are shown in red, patients with stable disease (SD) are shown in
light blue, and patients with complete response (CR) are shown in
blue.
[0049] FIG. 7B is a graphical representation of therapy scores
calculated for patients treated with an anti-CTLA4 therapy
(Ipililumab), in accordance with some embodiments of the technology
described herein. Patients with progressive disease (PD) are shown
as a dark solid line, patients with stable disease (SD) are shown
as a light grey striped line, and patients with partial response
(PR) are shown in a dark grey striped line.
[0050] FIG. 7C is a graphical representation of therapy scores
calculated for patients treated with an anti-PD1 therapy
(Pembrolizumab), in accordance with some embodiments of the
technology described herein. Patients with progressive disease (PD)
are shown as a dark solid line, patients with stable disease (SD)
are shown as a light grey striped line, and patients with partial
response (PR) are shown in a dark grey striped line.
[0051] FIG. 8A is a graphical representation of therapy scores
calculated without additional weight optimization in a machine
learning-based optimization of biomarker importance, in accordance
with some embodiments of the technology described herein. Patients
with progressive disease (PD) are shown as a dark solid line,
patients with stable disease (SD) are shown as a light grey striped
line, and patients with partial response (PR) are shown in a dark
grey striped line.
[0052] FIG. 8B is a graphical representation of therapy scores
calculated with machine-adapted weights, in accordance with some
embodiments of the technology described herein. Patients with
progressive disease (PD) are shown as a dark solid line, patients
with stable disease (SD) are shown as a light grey striped line,
and patients with partial response (PR) are shown in a dark grey
striped line.
[0053] FIG. 8C is a graphical representation of biomarker
importance in terms of feature importance calculated with forest
regression algorithms, in accordance with some embodiments of the
technology described herein.
[0054] FIG. 8D is a graphical representation of biomarker weights
recalculated with a logistic regression model to improve prediction
of therapy response, in accordance with some embodiments of the
technology described herein.
[0055] FIG. 9 is a graphic illustrating different types of screens
that may be shown to a user of the software program.
[0056] FIG. 10 is a screenshot presenting the selected patient's
report including information related to the patient's sequencing
data, the patient, and the patient's cancer.
[0057] FIG. 11 is a screenshot presenting information related to
anti-PD1 immunotherapy provided in response to selecting anti-PD1
immunotherapy (as shown by highlighting) in the immunotherapy
biomarkers portion of the screen (as shown in the left panel).
[0058] FIG. 12 is a screenshot presenting selection of mutational
burden biomarker by a user.
[0059] FIG. 13 is a screenshot presenting information relating to
the mutational burden biomarker (as shown in the middle panel)
provided in response to the user selecting the mutational burden
biomarker.
[0060] FIG. 14 is a screenshot presenting clinical trial data
relating to anti-PD1 therapy effectivity in patients having stage
IV metastatic melanoma (as shown in the right panel) provided in
response to the user selecting anti-PD1 immunotherapy (as shown in
the left panel).
[0061] FIG. 15 is a block diagram of an illustrative computer
system that may be used in implementing some embodiments of the
technology described herein.
DETAILED DESCRIPTION
[0062] Currently, certain conventional therapy selection methods
allow for selection of a therapy based on a single parameter (or
biomarker) of an individual patient or tumor, the presence or
absence of which is correlated with treatment response or patient
survival. The inventors have appreciated that there are several
problems with this type of single-parameter methodology. The first
problem of such conventional therapy selection methods is their
weak predictive power when evaluating potential candidate
therapies. While a particular individual biomarker may be
predictive of the efficacy of a candidate therapy for one cohort
(or group) of subjects (e.g., patients), it may fail to do so for a
second or further cohorts (or groups). A second biomarker may be
predictive of the efficacy of the candidate therapy for a second or
further cohorts (or groups) of subjects (e.g., patients), but fail
to do so for the first cohort (or group). Thus, different
individual biomarkers may suggest different courses of action. As a
result, using a single biomarker to determine the efficacy of a
candidate treatment is problematic for many patients. Even if a
single biomarker having the highest correlation with response for a
candidate treatment were chosen, it may still have a weak
predictive capability without taking into account the full scope of
each patient's case and personal condition.
[0063] Another problem with conventional single-parameter
methodology is the heterogeneity of a biomarker's values. Due to
the variation in measurements of different clinics and clinical
trials, potential biomarkers become incomparable between subjects
(e.g., patients) from different hospitals or clinical settings. The
biomarker values defined in one study could significantly differ
from the results of the same measurements performed at a different
site or on different equipment. While the relative meaning of a
biomarker may remain unchanged--for example, a "high" biomarker
value is bad or "low" value is good for predicting therapy
efficacy--experimental cut-off or threshold values for "high" or
"low" definitions often significantly vary among studies.
[0064] The inventors have developed techniques for predicting the
efficacy of therapies for a subject that address (e.g., mitigate or
avoid) the above-described problems of conventional
single-biomarker approaches. In particular, the inventors have
developed techniques of predicting therapy efficacy using multiple
biomarkers (e.g., biomarkers associated with positive therapeutic
response or non-positive therapeutic response to a particular
therapy or type of therapy). The inventors have appreciated that
different biomarkers may have values in vastly different ranges. In
order to use multiple such biomarkers in a single common
quantitative framework for predicting therapy efficacy, the
inventors have developed a technique for normalizing the values of
the biomarkers relative to their variation in reference
populations, thereby placing them on a common scale. The inventors
have also recognized that comparing biomarker scores of a patient
to those of other patients may be used to compute normalized
biomarker scores. Further, such normalized biomarker scores may be
utilized to more accurately predict a patient's response to a
therapy. The inventors have specifically developed techniques for
simultaneous analysis of the normalized biomarkers as described
herein.
[0065] Additionally, recent advances in personalized genomic
sequencing and cancer genomic sequencing technologies have made it
possible to obtain patient-specific information about cancer cells
(e.g., tumor cells) and cancer microenvironments from one or more
biological samples obtained from individual patients. This
information can be used to determine a large number of parameters
(or biomarkers) for each patient and, potentially, use this
information to identify effective therapies and/or select one or
more effective therapies for the subject (e.g., the patient). This
information may also be used to determine how a subject (e.g., a
patient) is responding over time to a treatment and, if necessary,
to select a new therapy or therapies for the subject (e.g., the
patient) as necessary. This information may also be used to
determine whether the subject (e.g., the patient) should be
included or excluded from participating in a clinical trial.
[0066] Global comparison of different types and groupings of
biomarkers using normalization as described herein was not known in
the art, and the integration of such normalized biomarkers in a
coherent and quantitative manner with therapy or impact scores
calculated therefrom provide more accurate predictions (greater
predictive capacity) of a patient's response to a therapy than
might be seen by the use of any single marker or less complex
combination of elements. The methods, systems, and graphical user
interfaces (GUIs) based on such a wide variety of biomarkers as
described herein are newly available and not previously described
techniques or methods existed to perform the elements of these
techniques. Further, techniques for combining various types of
biomarkers in a single analytical tool had not been developed
because these biomarkers were from different origins (i.e.,
different studies, hospitals, and treatment centers) and were of
vastly differing scales.
[0067] The inventors have recognized that several of the elements
described herein add something more than what is well understood,
routine, or conventional activity proposed by others in the field.
These meaningful non-routine steps result in the improvements seen
in the methods, systems, and GUIs described herein and include, but
are not limited to: the normalization of different biomarker types
to a common scale; the combination(s) of biomarker types provided
herein; the determination of therapy scores from different
biomarker types; technical improvements in analyses that allow for
more accurate prediction of a patient's response to a therapy and
resulting improvements in outcome for the patient; and the creation
of improved graphical user interfaces to aid in the selection of a
therapy.
[0068] Therefore, aspects of the technology described herein relate
to systems and methods and for predicting a patient's response to a
therapy based on patient specific information such as a patient's
biomarker values. In some embodiments, predicting a patient's
response to a therapy comprises determining normalized biomarker
scores (also described as "normalized scores") using sequencing
data and biomarker information. In some embodiments, predicting a
patient's response to a therapy comprises determining therapy
scores for the multiple therapies based on normalized biomarker
scores. A therapy score for a therapy is a numerical value that may
provide a quantitative measure of the therapy's predicted efficacy
in treating a subject. In some embodiments, determining a patient's
response to a therapy comprises determining an impact score based
on normalized biomarker scores. An impact score for a therapy is a
numerical value that may provide a quantitative measure of the
therapy's current efficacy (impact) in treating a subject.
[0069] Such methods and systems may be useful for clinical purposes
including, for example, selecting a treatment, evaluating
suitability of a patient for participating in a clinical trial, or
determining a course of treatment for a subject (e.g., a
patient).
[0070] The methods and systems described herein may also be useful
for non-clinical applications including (as a non-limiting example)
research purposes such as, e.g., studying the biological pathways
and/or biological processes targeted by a therapy, and developing
new therapies for cancer based on such studies.
[0071] Further, systems which present this information in a
comprehensive and useable format will be needed to facilitate
treatment of patients with such conditions. Therefore, provided
herein are systems and methods for analyzing patient specific
information that result in a prediction of a patient's response or
lack thereof to a treatment.
[0072] Such an analysis takes into consideration a global view of
patient information to make a prediction regarding the patient's
response to a therapy that is well-informed and comprehensive. The
analysis described herein, in some embodiments, is a global
analysis of patient specific information. Certain aspects of the
described methods take into account biological data generated from
analysis of at least one biological sample of a subject. Other
aspects of the described methods take into account patient specific
information related to the overall health and/or lifestyle of a
patient (e.g., personal habits, environmental factors) that may
play a role in whether a patient responds to a therapy.
[0073] Generally, techniques described herein provide for
improvements over conventional computer-implemented techniques for
analysis of medical data such as evaluation of expression data
(e.g., RNA expression data) and determining whether one or more
therapies (e.g., targeted therapies, radiotherapies, and/or
immunotherapies) will be effective in treating the subject. Such
improvements include, but are not limited to, improvements in
predictive power regarding the effectiveness of candidate
treatments for a subject over conventional single biomarker
treatments. Additionally, some embodiments of the technology
provided herein are directed to graphical user interfaces that
present oncological data in a new way which is compact and highly
informative. These graphical user interfaces not only reduce the
cognitive load on a user (e.g., a doctor or other medical
professional) working with them, but may serve to reduce clinician
errors and improve the functionality of a computer by providing all
needed information in a single interactive interface. This could
eliminate the need for a user (e.g., a clinician) to consult
different sources of information (e.g., view multiple different
webpages, use multiple different application programs, etc.), which
would otherwise place an additional burden on the processing,
memory, and communications resources of the computer(s) used by
such a user (e.g., a clinician).
Biomarkers
[0074] The methods described are based on in part on the analysis
of anthropometric, clinical, tumor, and/or cancerous cell
microenvironment parameters, and tumor and/or cancerous cell
parameters of a subject (e.g., a patient), along with accompanying
disease information. For such analyses, sequence data such as that
from transcriptome, exome, and/or genome sequencing of a patient's
tumor biopsy, or from other tissues of the patient are suitable
although any type of sequence data may be used. Additional data
concerning other patient, cancerous cell, or tumor parameters, or
microenvironment parameters may also be considered including, but
not limited to: tumor and/or cancerous cell proteomic analysis;
immunohistochemistry staining; flow cytometry; standard clinical
measurements of blood, urine and other biological fluids; biopsies
of one or more tumors and organs; images obtained by any methods,
including X-ray, ultrasonic, sonic, or magnetic resonance imaging
scintillation studies, etc. In these terms, all features that
distinguish one patient from another including, but not limited to,
disease stage, sex, age, tumor mutations, cancerous cell mutations,
blood analysis, IHC of biopsy, etc. are called patient parameters
and may be included in the algorithm. The parameters of the subject
(e.g., the patient), the type of tumor, or the type of cancerous
cell may have been identified in group clinical trials that were
published in scientific journals or actively used in clinically
approved analyses, guidelines of treatment options (FDA, NIH, NCCN,
CPIC, etc.) or elsewhere. These parameters are biomarkers, the
presence or absence of which and/or levels of which may be
statistically significantly correlated (e.g., the correlation may
be at least a threshold amount away from zero) with treatment
response or patient survival.
[0075] Certain techniques described herein are designed to use any
reliable and available information about discovered biomarkers to
simultaneously analyze individual biomarkers of the patient and may
use any number of pre-defined biomarker combinations. This method
generally considers several parameters concerning the patient
and/or the cancerous tissues and/or cells of the patient and does
not classify the patient to a one-biomarker group, such as high or
low PDL1 expression. Certain techniques described herein may be
based on the simultaneous analysis of tens or hundreds of
biomarkers.
[0076] In some embodiments, the techniques described herein provide
a way to generate "thresholds" for pre-defined biomarkers based on
(e.g., large volumes of) data obtained from large numbers of
patients, such as TCGA, ICGC, Human Protein Atlas, etc., allowing
for the creation of a normalized score for each of the biomarkers.
Combinations of normalized biomarker scores for the patient may be
used to analyze one more defined therapies (creating therapy
scores) providing information that allows the selection of one or
more therapies for each patient based on their personal
parameters.
Types of Biomarkers
[0077] Aspects of the present disclosure relate to systems and
methods for predicting efficacy of a cancer treatment from a
plurality of biomarkers. As used herein, the term "biomarker"
refers to any information (or any parameter) of a biomolecule
(e.g., a gene or a protein), a cancer (e.g., tumor type) or a
subject (e.g., age of a subject) that may be used to predict an
effect of a therapy or lack thereof in the subject. Accordingly,
"biomarker information" or "biomarker value" as used herein, refers
to any information relating to a biomarker. As a non-limiting
example, if a biomarker is age, a biomarker value (e.g.,
information about the biomarker) may be 32 for a patient that is 32
years of age.
[0078] A biomarker as described herein may be associated with at
least one therapy and/or at least one cancer. As used herein, the
term "associated with" indicates that a biomarker has been found to
be relevant (e.g., in one or more studies such as those described
in a paper or journal article) to and/or involved with the
associated therapy and/or the associated cancer. It should be
appreciated that a biomarker, in some embodiments, may be directly
linked to a therapy and/or cancer or indirectly linked to a therapy
and/or a cancer (e.g., that the biomarker has been found to
directly or indirectly effect or modulate a biological process
related to the therapy and/or the cancer). As a set of non-limiting
examples, biomarkers for use with the methods and systems described
herein may include any group or subset of biomarkers listed herein,
including those listed in the Tables (e.g., in Table 2). Such a
group or subset of biomarkers may include at least 3, at least 4,
at least 5, at least 6, at least 7, at least 8, at least 9, at
least 10, at least 20, at least 30, at least 40, at least 50, at
least 60, at least 70, at least 80, at least 90, at least 100, at
least 200, at least 300, at least 400, at least 500, at least 600,
at least 700, at least 800, at least 900, or at least 1000
biomarkers. Such a group or subset of biomarkers may include up to
3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10,
up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to
80, up to 90, up to 100, up to 200, up to 300, up to 400, up to
500, up to 600, up to 700, up to 800, up to 900, or up to 1000
biomarkers.
[0079] A biomarker as described herein, in some embodiments, may be
associated with multiple therapies. In some embodiments, a
biomarker may be associated with at least 2, at least 3, at least
4, at least 5, at least 6, at least 7, at least 8, at least 9, at
least 10, at least 20, at least 30, at least 40, at least 50, at
least 60, at least 70, at least 80, at least 90, or at least 100
different therapies. In some embodiments, a biomarker may be
associated with up to 2, up to 3, up to 4, up to 5, up to 6, up to
7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to
50, up to 60, up to 70, up to 80, up to 90, or up to 100 different
therapies.
[0080] A biomarker as described herein, in some embodiments, may be
associated with multiple cancers. In some embodiments, a biomarker
may be associated with at least 2, at least 3, at least 4, at least
5, at least 6, at least 7, at least 8, at least 9, at least 10, at
least 20, at least 30, at least 40, at least 50, at least 60, at
least 70, at least 80, at least 90, or at least 100 different
cancers. In some embodiments, a biomarker may be associated with up
to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to
9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up
to 70, up to 80, up to 90, or up to 100 different cancers.
[0081] Biomarkers as provided herein may be associated with any
biomolecule. Examples of a biomolecule include, but are not limited
to, a growth factor, a hormone, a steroid, a saccharide, a lipid, a
heterocyclic compound, an elementary compound (e.g., iron), a
metabolite, a vitamin, a neurotransmitter, and fatty acids. Such
biomarkers may be referred to by the biomolecule that they are
associated with. For example, a biomarker associated with a
saccharide may be referred to as a saccharide biomarker; a
biomarker associated with a lipid may be referred to as a lipid
biomarker; a biomarker associated with a heterocyclic compound may
be referred to as a heterocyclic biomarker, and a biomarker
associated with an elementary compound may be referred to as an
elementary compound biomarker.
[0082] A "genetic biomarker," as used herein, is a biomarker
associated with a gene or any product thereof (e.g., RNA, protein).
Examples of a genetic biomarker include, but are not limited to, a
gene expression level (e.g., an increased expression level or a
decreased expression level), a gene mutation, a gene insertion, a
gene deletion, a gene fusion, a single nucleotide polymorphism
(SNPs), and a gene copy number variation (CNV).
[0083] A genetic biomarker as described herein may be associated
with any gene. In some embodiments, genes are group by a related
function and/or other property. Examples of gene groups include,
but are not limited to, the fibroblasts group, the angiogenesis
group, the tumor properties group, the anti-tumor immune
microenvironment group, the tumor-promoting immune microenvironment
group, the cancer associated fibroblasts group, the proliferation
rate group, the PI3K/AKT/mTOR signaling group, the RAS/RAF/MEK
signaling group, the receptor tyrosine kinases expression group,
the tumor suppressors group, the metastasis signature group, the
anti-metastatic factors group, the mutation status group, the
antigen presentation group, the cytotoxic T and NK cells group, the
B cells group, the anti-tumor microenvironment group, the
checkpoint inhibition group, the Treg group, the MDSC group, the
granulocytes group, the tumor-promotive immune group, the receptor
tyrosine kinases expression group, the growth factors group, the
tumor suppressors group, the metastasis signature group, the
anti-metastatic factors group, the mutation status group, the MHCI
group, the MHCII group, the coactivation molecules group, the
effector cells group, the NK cells group, the T cell traffic group,
the T cells group, the M1 signatures group, the Th1 signature
group, the antitumor cytokines group, the checkpoint inhibition
group, the M2 signature group, the Th2 signature group, the
protumor cytokines group, and the complement inhibition group.
[0084] In some embodiments, a genetic biomarker may be associated
with some (e.g., at least three) genes from one or more of the
following groups: the fibroblasts group: LGALS1, COL1A1, COL1A2,
COL4A1, COL5A1, TGFB1, TGFB2, TGFB3, ACTA2, FGF2, FAP, LRP1, CD248,
COL6A1, COL6A2, and COL6A3; the angiogenesis group: VEGFA, VEGFB,
VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2,
TEK, VWF, CDH5, NOS3, KDR, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9,
SPP1, LOX, SLC2A1, and LAMP3; the tumor properties group: MKI67,
ESCO2, CETN3, CDK2, CCND1, CCNE1, AURKA, AURKB, CDK4, CDK6, PRC1,
E2F1, MYBL2, BUB1, PLK1, CCNB1, MCM2, MCM6, PIK3CA, PIK3CB, PIK3CG,
PIK3CD, AKT1, MTOR, PTEN, PRKCA, AKT2, AKT3, BRAF, FNTA, FNTB,
MAP2K1, MAP2K2, MKNK1, MKNK2, ALK, AXL, KIT, EGFR, ERBB2, FLT3,
MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA,
PDGFRB, NGF, CSF3, CSF2, FGF7, IGF1, IGF2, IL7, FGF2, TP53, SIK1,
PTEN, DCN, MTAP, AIM2, RB1, ESRP1, CTSL, HOXA1, SMARCA4, SNAI2,
TWIST1, NEDD9, PAPPA, HPSE, KISS1, ADGRG1, BRMS1, TCF21, CDH1,
PCDH10, NCAM1, MITF, APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2,
CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS,
IDH1, KRAS, MAP3K1, MTOR, NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS,
PBRM1, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53,
and VHL; the anti-tumor immune microenvironment group: HLA-A,
HLA-B, HLA-C, B2M, TAP1, TAP2, HLA-DRA, HLA-DRB1, HLA-DOB,
HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DMB, HLA-DQB1,
HLA-DQA1, HLA-DRB5, HLA-DQA2, HLA-DQB2, HLA-DRB6, CD80, CD86, CD40,
CD83, TNFRSF4, ICOSLG, CD28, IFNG, GZMA, GZMB, PRF1, LCK, GZMK,
ZAP70, GNLY, FASLG, TBX21, EOMES, CD8A, CD8B, NKG7, CD160, CD244,
NCR1, KLRC2, KLRK1, CD226, GZMH, GNLY, IFNG, KIR2DL4, KIR2DS1,
KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, CXCL9, CXCL10, CXCR3, CX3CL1,
CCR7, CXCL11, CCL21, CCL2, CCL3, CCL4, CCL5, EOMES, TBX21, ITK,
CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK, UBASH3A, TRAT1, CD19,
MS4A1, TNFRSF13C, CD27, CD24, CR2, TNFRSF17, TNFRSF13B, CD22,
CD79A, CD79B, BLK, NOS2, IL12A, IL12B, IL23A, TNF, IL1B, SOCS3,
IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, IL21, HMGB1, TNF, IFNB1,
IFNA2, CCL3, TNFSF10, and FASLG; the tumor-promoting immune
microenvironment group: PDCD1, CD274, CTLA4, LAG3, PDCD1LG2, BTLA,
HAVCR2, VSIR, CXCL12, TGFB1, TGFB2, TGFB3, FOXP3, CTLA4, IL10,
TNFRSF1B, CCL17, CXCR4, CCR4, CCL22, CCL1, CCL2, CCL5, CXCL13,
CCL28, IDO1, ARG1, IL4R, IL10, TGFB1, TGFB2, TGFB3, NOS2, CYBB,
CXCR4, CD33, CXCL1, CXCL5, CCL2, CCL4, CCL8, CCR2, CCL3, CCL5,
CSF1, CXCL8, CXCL8, CXCL2, CXCL1, CCL11, CCL24, KITLG, CCL5, CXCL5,
CCR3, CCL26, PRG2, EPX, RNASE2, RNASE3, IL5RA, GATA1, SIGLEC8,
PRG3, CMA1, TPSAB1, MS4A2, CPA3, IL4, IL5, IL13, SIGLEC8, MPO,
ELANE, PRTN3, CTSG, IL10, VEGFA, TGFB1, IDO1, PTGES, MRC1, CSF1,
LRP1, ARG1, PTGS1, MSR1, CD163, CSF1R, IL4, IL5, IL13, IL10, IL25,
GATA3, IL10, TGFB1, TGFB2, TGFB3, IL22, MIF, CFD, CFI, CD55, CD46,
and CR1; the cancer associated fibroblasts group: LGALS1, COL1A1,
COL1A2, COL4A1, COL5A1, TGFB1, TGFB2, TGFB3, ACTA2, FGF2, FAP,
LRP1, CD248, COL6A1, COL6A2, and COL6A3; the angiogenesis group:
VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR,
ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, KDR, VCAM1, MMRN1, LDHA,
HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3; the proliferation
rate group: MKI67, ESCO2, CETN3, CDK2, CCND1, CCNE1, AURKA, AURKB,
CDK4, CDK6, PRC1, E2F1, MYBL2, BUB1, PLK1, CCNB1, MCM2, and MCM6;
the PI3K/AKT/mTOR signaling group: PIK3CA, PIK3CB, PIK3CG, PIK3CD,
AKT1, MTOR, PTEN, PRKCA, AKT2, and AKT3; the RAS/RAF/MEK signaling
group: BRAF, FNTA, FNTB, MAP2K1, MAP2K2, MKNK1, and MKNK2; the
receptor tyrosine kinases expression group: ALK, AXL, KIT, EGFR,
ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3,
BCR-ABL, PDGFRA, and PDGFRB; the tumor suppressors group: TP53,
SIK1, PTEN, DCN, MTAP, AIM2, and RB1; the metastasis signature
group: ESRP1, CTSL, HOXA1, SMARCA4, SNAI2, TWIST1, NEDD9, PAPPA,
and HPSE; the anti-metastatic factors group: KISS1, ADGRG1, BRMS1,
TCF21, CDH1, PCDH10, NCAM1, and MITF; the mutation status group:
APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF,
CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS, IDH1, KRAS, MAP3K1,
MTOR, NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS, PBRM1, PIK3CA, PIK3R1,
PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53, and VHL; the antigen
presentation group: HLA-A, HLA-B, HLA-C, B2M, TAP1, TAP2, HLA-DRA,
HLA-DRB1, HLA-DOB, HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1,
HLA-DMB, HLA-DQB1, HLA-DQA1, HLA-DRB5, HLA-DQA2, HLA-DQB2,
HLA-DRB6, CD80, CD86, CD40, CD83, TNFRSF4, ICOSLG, and CD28; the
cytotoxic T and NK cells group: IFNG, GZMA, GZMB, PRF1, LCK, GZMK,
ZAP70, GNLY, FASLG, TBX21, EOMES, CD8A, CD8B, NKG7, CD160, CD244,
NCR1, KLRC2, KLRK1, CD226, GZMH, GNLY, IFNG, KIR2DL4, KIR2DS1,
KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, CXCL9, CXCL10, CXCR3, CX3CL1,
CCR7, CXCL11, CCL21, CCL2, CCL3, CCL4, CCL5, EOMES, TBX21, ITK,
CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK, UBASH3A, and TRAT1; the
B cells group: CD19, MS4A1, TNFRSF13C, CD27, CD24, CR2, TNFRSF17,
TNFRSF13B, CD22, CD79A, CD79B, and BLK; the anti-tumor
microenvironment group: NOS2, IL12A, IL12B, IL23A, TNF, IL1B,
SOCS3, IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, IL21, HMGB1, TNF,
IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the checkpoint inhibition
group: PDCD1, CD274, CTLA4, LAGS, PDCD1LG2, BTLA, HAVCR2, and VSIR;
the Treg group: CXCL12, TGFB1, TGFB2, TGFB3, FOXP3, CTLA4, IL10,
TNFRSF1B, CCL17, CXCR4, CCR4, CCL22, CCL1, CCL2, CCL5, CXCL13, and
CCL28; the MDSC group: IDO1, ARG1, IL4R, IL10, TGFB1, TGFB2, TGFB3,
NOS2, CYBB, CXCR4, CD33, CXCL1, CXCL5, CCL2, CCL4, CCL8, CCR2,
CCL3, CCL5, CSF1, and CXCL8; the granulocytes group: CXCL8, CXCL2,
CXCL1, CCL11, CCL24, KITLG, CCL5, CXCL5, CCR3, CCL26, PRG2, EPX,
RNASE2, RNASE3, IL5RA, GATA1, SIGLEC8, PRG3, CMA1, TPSAB1, MS4A2,
CPA3, IL4, IL5, IL13, SIGLEC8, MPO, ELANE, PRTN3, and CTSG; the
tumor-promotive immune group: IL10, VEGFA, TGFB1, IDO1, PTGES,
MRC1, CSF1, LRP1, ARG1, PTGS1, MSR1, CD163, CSF1R, IL4, IL5, IL13,
IL10, IL25, GATA3, IL10, TGFB1, TGFB2, TGFB3, IL22, MIF, CFD, CFI,
CD55, CD46, and CR1; the receptor tyrosine kinases expression
group: ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2,
FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, and PDGFRB; the growth
factors group: NGF, CSF3, CSF2, FGF7, IGF1, IGF2, IL7, and FGF2;
the tumor suppressors group: TP53, SIK1, PTEN, DCN, MTAP, AIM2, and
RB1; the metastasis signature group: ESRP1, CTSL, HOXA1, SMARCA4,
SNAI2, TWIST1, NEDD9, PAPPA, and HPSE; the anti-metastatic factors
group: KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, and MITF;
the mutation status group: APC, ARID1A, ATM, ATRX, BAP1, BRAF,
BRCA2, CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3,
GATA3, HRAS, IDH1, KRAS, MAP3K1, MTOR, NAV3, NCOR1, NF1, NOTCH1,
NPM1, NRAS, PBRM1, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, SETD2, STAG2,
TAF1, TP53, and VHL; the MHCI group: HLA-A, HLA-B, HLA-C, B2M,
TAP1, and TAP2; the MHCII group: HLA-DRA, HLA-DRB1, HLA-DOB,
HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DMB, HLA-DQB1,
HLA-DQA1, HLA-DRB5, HLA-DQA2, HLA-DQB2, and HLA-DRB6; the
coactivation molecules group: CD80, CD86, CD40, CD83, TNFRSF4,
ICOSLG, and CD28; the effector cells group: IFNG, GZMA, GZMB, PRF1,
LCK, GZMK, ZAP70, GNLY, FASLG, TBX21, EOMES, CD8A, and CD8B; the NK
cells group: NKG7, CD160, CD244, NCR1, KLRC2, KLRK1, CD226, GZMH,
GNLY, IFNG, KIR2DL4, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, and
KIR2DS5; the T cell traffic group: CXCL9, CXCL10, CXCR3, CX3CL1,
CCR7, CXCL11, CCL21, CCL2, CCL3, CCL4, and CCL5; the T cells group:
EOMES, TBX21, ITK, CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK,
UBASH3A, and TRAT1; the M1 signatures group: NOS2, IL12A, IL12B,
IL23A, TNF, IL1B, and SOCS3; the Th1 signature group: IFNG, IL2,
CD40LG, IL15, CD27, TBX21, LTA, and IL21; the antitumor cytokines
group: HMGB1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the M2
signature group: IL10, VEGFA, TGFB1, IDO1, PTGES, MRC1, CSF1, LRP1,
ARG1, PTGS1, MSR1, CD163, and CSF1R; the Th2 signature group: IL4,
IL5, IL13, IL10, IL25, and GATA3; the protumor cytokines group:
IL10, TGFB1, TGFB2, TGFB3, IL22, and MIF; and the complement
inhibition group: CFD, CFI, CD55, CD46, and CR1.
[0085] A "protein biomarker," as used herein, is a biomarker
associated with a protein. Examples of a protein biomarker include,
but are not limited to, a protein expression level (e.g., an
increased expression level or a decreased expression level), a
protein activity level (e.g., an increased activity level or a
decreased activity level), a protein mutation, and a protein
truncation.
[0086] A protein biomarker as described herein may associated with
any protein. Examples of proteins related to protein biomarkers
include, but are not limited to, interferons, cytotoxic proteins,
enzymes, cell adhesion proteins, extracellular matrix proteins,
transcription factor proteins, intracellular signaling proteins,
cytokines, chemokines, chemokine receptors, and interleukins. Such
biomarkers may be referred to by the biomolecule for which they are
related to, for example, interferon biomarker, cytotoxic protein
biomarker, enzyme biomarker, cell adhesion protein biomarker,
extracellular matrix protein biomarker, transcription factor
protein biomarker, intracellular signaling protein biomarker,
cytokine biomarker, chemokine biomarker, chemokine receptor
biomarker, and interleukin biomarker. Such protein biomarkers may
include products of, for example, any of the genes listed or
referred to herein.
[0087] A "cellular biomarker," as used herein, is a biomarker
associated with a cell. Examples of cellular biomarkers include,
but are not limited to, numbers of types of one or more cells,
percentage of one or more types of cells, location of one or more
cells, and structure or morphology of one or more cells.
[0088] A cellular biomarker as described herein may be associated
with any cell. Examples of cells include, but are not limited to,
malignant cancer cells, leukocytes, lymphocytes, stromal cells,
vascular endothelial cells, vascular pericytes, and myeloid-derived
suppressor cells (MDSCs).
[0089] An "expression biomarker," as used herein, is a biomarker
associated with an expression of a gene or a product thereof (e.g.,
RNA, protein). Examples of expression biomarkers include, but are
not limited to, an increased expression level of a gene or product
thereof, a decreased expression level of a gene or product thereof,
expression of a truncated gene or product thereof, and expression
of a mutated gene or product thereof.
[0090] By comparing the expression level of a biomarker in a sample
obtained from a subject to a reference (or control), it can be
determined whether the subject has an altered expression level
(e.g., increased or decreased) as compared to the reference (or
control). For example, if the level of a biomarker in a sample from
a subject deviates (e.g., is increased or decreased) from the
reference value (by e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more from a
reference value), the biomarker might be identified as an
expression biomarker.
[0091] An "imaging biomarker," as used herein, is a biomarker
associated with imaging data. Examples of imaging biomarkers
include, but are not limited to, expression levels obtained from
imaging data, numbers of types of one or more cells obtained from
imaging data, and cancer location and/or progression obtained from
imaging data.
[0092] An imaging biomarker as described herein may be associated
with any imaging data. Examples of imaging data include, but are
not limited to, histological imaging data, immunohistological
imaging data, magnetic resonance imaging (MRI) data, ultrasound
data, and x-ray data.
[0093] A "disease-state biomarker," as used herein, is a biomarker
associated with a state of a disease (e.g., cancer). Examples of
disease-state biomarkers include, but are not limited to,
metastasis status (e.g., absence or presence of metastasis),
remission status (e.g., number of previous remissions, current
remission), disease progression (e.g., low, moderate, or high
disease progression), and cancer stage (e.g., stage 1, stage 2,
stage 3, or stage 4).
[0094] Biomarkers as used herein encompasses any patient specific
information that may be used to predict that patient's response to
a therapy. For example, a personal habit of a patient (e.g.,
smoking) may be used as a biomarker to predict whether the patient
is a responder or non-responder to a therapy.
[0095] A "personal habit biomarker," as used herein, is a biomarker
associated with a personal habit of a subject. Examples of personal
habit biomarkers include, but are not limited to, smoking (e.g.,
status as a smoker or non-smoker), frequency of exercise, alcohol
use (e.g., low, moderate, high use of alcohol), and drug use (e.g.,
low, moderate, high use of drugs).
[0096] In another example, a cultural or environmental factor
experienced by a patient may play a role in whether the patient
responds to a therapy. Such factors are used in systems and methods
described herein to predict a patient's response to a therapy.
[0097] An "anthropological biomarker," as used herein, is a
biomarker associated with a culture and/or an environment of a
subject. Examples of anthropological biomarkers include, but are
not limited to, stress (e.g., low, moderate, or high stress
levels), economic status (e.g., low, moderate, or high economic
status), mental health (e.g., depression or anxiety), and
relationship status (e.g., married, single, divorced, or
widowed).
From Biomarker Values to Normalized Biomarker Scores
[0098] Aspects of the present disclosure provide systems and
methods that normalize biomarker scores to a common scale, thereby
allowing comparison of biomarker scores across different cell
populations and/or among different subjects.
[0099] Normalized biomarker scores may be determined for any number
of biomarkers as described herein. As used herein, the term
"normalized biomarker score" refers to a biomarker value that has
been adjusted (e.g., normalized) to a common scale according to the
techniques described herein.
[0100] In some embodiments, biomarker values are normalized to
create normalized biomarker scores based on a respective
distribution of values for each biomarker in a reference subset of
biomarkers. In some embodiments, the reference subset of biomarkers
comprises biomarker information from any number of reference
subjects. In one embodiment, a "reference subset" is a subset of
biomarkers from one or more reference subjects, the values of which
may be used to normalize a biomarker of a subject.
[0101] As a non-limiting example, data may be available for up to
4,000 biomarkers for a group of subjects. In this group of 4,000
biomarkers, 1,000 biomarkers may be associated with a particular
therapy (thus creating a reference subset of 1,000 biomarkers). If,
for a particular subject being analyzed using the methods and
systems described herein, values for 723 of these biomarkers are
available (thus creating a subject subset of 723 biomarkers), a
normalized biomarker score for each of the 723 biomarkers may be
computed using the distribution of values for each particular
biomarker. As another non-limiting example, in this group of 4,000
biomarkers, 10 biomarkers may be associated with a particular
therapy (thus creating a reference subset of 10 biomarkers). If,
for a particular subject being analyzed using the methods and
systems described herein, values for 7 of these biomarkers are
available (thus creating a subject subset of 7 biomarkers), a
normalized biomarker score for each of the 7 biomarkers may be
computed using the distribution of values for each particular
biomarker.
[0102] In some embodiments, the reference subset of biomarkers
comprises biomarker information from any number of subjects. In
some embodiments, the reference subset of biomarkers comprises
biomarker information from at least 1, at least 2, at least 3, at
least 4, at least 5, at least 6, at least 7, at least 8, at least
9, at least 10, at least 11, at least 12, at least 13, at least 14,
at least 15, at least 16, at least 17, at least 18, at least 19, at
least 20, at least 25, at least 30, at least 35, at least 40, at
least 45, at least 50, at least 55, at least 60, at least 65, at
least 70, at least 75, at least 80, at least 85, at least 90, at
least 95, at least 100, at least 200, at least 300, at least 400,
at least 500, or at least 1000 subjects. In some embodiments, the
reference subset of biomarkers comprises biomarker information from
up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up
to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15,
up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to
30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up
to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95,
up to 100, up to 200, up to 300, up to 400, up to 500, or up to
1000 subjects.
[0103] A reference subset of biomarkers may comprise any number of
biomarkers. In some embodiments, the reference subset of biomarkers
comprises at least 1, at least 2, at least 3, at least 4, at least
5, at least 6, at least 7, at least 8, at least 9, at least 10, at
least 11, at least 12, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, at
least 25, at least 30, at least 35, at least 40, at least 45, at
least 50, at least 55, at least 60, at least 65, at least 70, at
least 75, at least 80, at least 85, at least 90, at least 95, at
least 100, at least 200, at least 300, at least 400, at least 500,
or at least 1000 biomarkers. In some embodiments, the reference
subset of biomarkers comprises up to 2, up to 3, up to 4, up to 5,
up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12,
up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to
19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up
to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80,
up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up
to 400, up to 500, or up to 1000 biomarkers.
[0104] In some embodiments, biomarker values are normalized to
create normalized biomarker scores based on a respective
distribution of values for each biomarker in a subject subset of
biomarkers. As used herein, the "subject subset" of biomarkers
comprises biomarker information from a single subject. A subject
subset of biomarkers may comprise any number of biomarkers. In some
embodiments, the subject subset of biomarkers comprises at least 1,
at least 2, at least 3, at least 4, at least 5, at least 6, at
least 7, at least 8, at least 9, at least 10, at least 11, at least
12, at least 13, at least 14, at least 15, at least 16, at least
17, at least 18, at least 19, at least 20, at least 25, at least
30, at least 35, at least 40, at least 45, at least 50, at least
55, at least 60, at least 65, at least 70, at least 75, at least
80, at least 85, at least 90, at least 95, at least 100, at least
200, at least 300, at least 400, at least 500, or at least 1000
biomarkers. In some embodiments, the subject subset of biomarkers
comprises up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up
to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up
to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25,
up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to
60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up
to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up
to 1000 biomarkers. In some embodiments, the subject subset of
biomarkers is identical to the reference subset of biomarkers
(i.e., for a given calculation, system, or method described
herein).
[0105] Systems and methods described herein provide for determining
any number of normalized biomarker scores using sequencing data and
biomarker information. In some embodiments, systems and methods
described herein provide for determining at least 1, at least 2, at
least 3, at least 4, at least 5, at least 6, at least 7, at least
8, at least 9, at least 10, at least 11, at least 12, at least 13,
at least 14, at least 15, at least 16, at least 17, at least 18, at
least 19, at least 20, at least 25, at least 30, at least 35, at
least 40, at least 45, at least 50, at least 55, at least 60, at
least 65, at least 70, at least 75, at least 80, at least 85, at
least 90, at least 95, at least 100, at least 200, at least 300, at
least 400, at least 500, or at least 1000 normalized biomarker
scores. In some embodiments, systems and methods described herein
provide for determining up to 2, up to 3, up to 4, up to 5, up to
6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to
13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up
to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50,
up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to
85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400,
up to 500, or up to 1000 normalized biomarker scores.
[0106] Systems and methods described herein, in some embodiments,
provide for determining normalized biomarker scores for biomarkers
associated with a particular therapy. In some embodiments, systems
and methods described herein provide for determining normalized
biomarker scores for at least 1, at least 2, at least 3, at least
4, at least 5, at least 6, at least 7, at least 8, at least 9, at
least 10, at least 11, at least 12, at least 13, at least 14, at
least 15, at least 16, at least 17, at least 18, at least 19, at
least 20, at least 25, at least 30, at least 35, at least 40, at
least 45, at least 50, at least 55, at least 60, at least 65, at
least 70, at least 75, at least 80, at least 85, at least 90, at
least 95, at least 100, at least 200, at least 300, at least 400,
at least 500, or at least 1000 biomarkers associated with a
particular therapy. In some embodiments, systems and methods
described herein provide for determining normalized biomarker
scores for up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up
to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up
to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20,
up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to
55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up
to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to
500, or up to 1000 biomarkers associated with a particular
therapy.
[0107] Systems and methods for normalization of biomarkers as
described herein may be applied to biomarkers for any cancer (e.g.,
any tumor). Exemplary cancers include, but are not limited to,
adrenocortical carcinoma, bladder urothelial carcinoma, breast
invasive carcinoma, cervical squamous cell carcinoma, endocervical
adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney
renal clear cell carcinoma, kidney renal papillary cell carcinoma,
liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous
cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic
adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma,
skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma,
uterine corpus endometrial carcinoma, any type of lymphoma,
leukemia, and cholangiocarcinoma.
Obtaining Biomarker Information
[0108] Biomarker information as described herein may be obtained
from a variety of sources. In some embodiments, biomarker
information may be obtained by analyzing a biological sample from a
patient. The biological sample may be analyzed prior to performance
of the methods described herein for predicting the efficacy of one
or more treatments for the patient. In some such embodiments, data
obtained from the biological sample may stored (e.g., in a
database) and accessed during performance of the techniques
described herein for predicting the efficacy of one or more
treatments for the patient. In some embodiments, biomarker
information is obtained from a database containing biomarker
information for at least one patient.
Biological Samples
[0109] Any biological sample from a subject (i.e., a patient or
individual) may be analyzed as described herein to obtain biomarker
information. In some embodiments, the biological sample may be any
sample from a subject known or suspected of having cancerous cells
or pre-cancerous cells.
[0110] The biological sample may be from any source in the
subject's body including, but not limited to, any fluid [such as
blood (e.g., whole blood, blood serum, or blood plasma), saliva,
tears, synovial fluid, cerebrospinal fluid, pleural fluid,
pericardial fluid, ascitic fluid, and/or urine], hair, skin
(including portions of the epidermis, dermis, and/or hypodermis),
oropharynx, laryngopharynx, esophagus, stomach, bronchus, salivary
gland, tongue, oral cavity, nasal cavity, vaginal cavity, anal
cavity, bone, bone marrow, brain, thymus, spleen, small intestine,
appendix, colon, rectum, anus, liver, biliary tract, pancreas,
kidney, ureter, bladder, urethra, uterus, vagina, vulva, ovary,
cervix, scrotum, penis, prostate, testicle, seminal vesicles,
and/or any type of tissue (e.g., muscle tissue, epithelial tissue,
connective tissue, or nervous tissue).
[0111] The biological sample may be any type of sample including,
for example, a sample of a bodily fluid, one or more cells, a piece
of tissue, or some or all of an organ. In certain embodiments, one
sample will be taken from a subject for analysis. In some
embodiments, more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, or more) samples may be taken
from a subject for analysis. In some embodiments, one sample from a
subject will be analyzed. In certain embodiments, more than one
(e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, or more) samples may be analyzed. If more than one sample
from a subject is analyzed, the samples may be procured at the same
time (e.g., more than one sample may be taken in the same
procedure), or the samples may be taken at different times (e.g.,
during a different procedure including a procedure 1, 2, 3, 4, 5,
6, 7, 8, 9, 10 days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks; 1, 2, 3,
4, 5, 6, 7, 8, 9, 10 months, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years,
or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 decades after a first procedure).
A second or subsequent sample may be taken or obtained from the
same region (e.g., from the same tumor or area of tissue) or a
different region (including, e.g., a different tumor). A second or
subsequent sample may be taken or obtained from the subject after
one or more treatments, and may be taken from the same region or a
different region. As a non-limiting example, the second or
subsequent sample may be useful in determining whether the cancer
in each sample has different characteristics (e.g., in the case of
samples taken from two physically separate tumors in a patient) or
whether the cancer has responded to one or more treatments (e.g.,
in the case of two or more samples from the same tumor or different
tumors prior to and subsequent to a treatment).
[0112] Any of the biological samples described herein may be
obtained from the subject using any known technique. In some
embodiments, the biological sample may be obtained from a surgical
procedure (e.g., laparoscopic surgery, microscopically controlled
surgery, or endoscopy), bone marrow biopsy, punch biopsy,
endoscopic biopsy, or needle biopsy (e.g., a fine-needle
aspiration, core needle biopsy, vacuum-assisted biopsy, or
image-guided biopsy). In some embodiments, each of the at least one
biological samples is a bodily fluid sample, a cell sample, or a
tissue biopsy.
[0113] In some embodiments, one or more than one cell (i.e., a cell
sample) may be obtained from a subject using a scrape or brush
method. The cell sample may be obtained from any area in or from
the body of a subject including, for example, from one or more of
the following areas: the cervix, esophagus, stomach, bronchus, or
oral cavity. In some embodiments, one or more than one piece of
tissue (e.g., a tissue biopsy) from a subject may be used. In
certain embodiments, the tissue biopsy may comprise one or more
than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10)
samples from one or more tumors or tissues known or suspected of
having cancerous cells.
Sample Analysis
[0114] Systems and methods described herein are based, at least in
part, on the identification and characterization of certain
biomarkers of a patient and/or the patient's cancer. Such
information may be obtained from a biological sample of the subject
(e.g., the patient) as described herein.
[0115] Any type of analysis may be performed on a biological sample
from a subject. In some embodiments, a blood analysis is performed
on a biological sample from a subject. In some embodiments, a
cytometry analysis is performed on a biological sample from a
subject. In some embodiments, a histological analysis is performed
on a biological sample from a subject. In some embodiments, a
immunohistological analysis is performed on a biological sample
from a subject.
[0116] Any type of sequencing data may be obtained from a
biological sample of a subject. In some embodiments, the sequencing
data is DNA sequencing data. In some embodiments, the sequencing
data is RNA sequencing data. In some embodiments, the sequencing
data is proteome sequencing data.
[0117] Such sequencing data may be obtained by any known technique.
In some embodiments, the sequencing data is obtained from whole
genome sequencing (WGS). In some embodiments, the sequencing data
is obtained from whole exome sequencing (WES). In some embodiments,
the sequencing data is obtained from whole transcriptome
sequencing. In some embodiments, the sequencing data is obtained
from mRNA sequencing. In some embodiments, the sequencing data is
obtained from DNA/RNA-hybridization. In some embodiments, the
sequencing data is obtained from microarray. In some embodiments,
the sequencing data is obtained from DNA/RNA chip. In some
embodiments, the sequencing data is obtained from PCR. In some
embodiments, the sequencing data is obtained from single nucleotide
polymorphism (SNP) genotyping.
[0118] Expression data (e.g., indicating expression levels) for a
plurality of genes may be obtained from a biological sample. There
is no limit to the number of genes which may be examined. For
example, there is no limit to the number of genes for which the
expression levels may be examined.
[0119] As a non-limiting example, four or more, five or more, six
or more, seven or more, eight or more, nine or more, ten or more,
eleven or more, twelve or more, 13 or more, 14 or more, 15 or more,
16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or
more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more,
27 or more, 28 or more, 29 or more, 30 or more, 40 or more, 50 or
more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more,
125 or more, 150 or more, 175 or more, 200 or more, 225 or more,
250 or more, 275 or more, or 300 or more genes may be used for any
evaluation described herein. As another set of non-limiting
examples, at least four, at least five, at least six, at least
seven, at least eight, at least nine, at least ten, at least
eleven, at least twelve, at least 13, at least 14, at least 15, at
least 16, at least 17, at least 18, at least 19, at least 20, at
least 21, at least 22, at least 23, at least 24, at least 25, at
least 26, at least 27, at least 28, at least 29, at least 30, at
least 40, at least 50, at least 60, at least 70, at least 80, at
least 90, at least 100, at least 125, at least 150, at least 175,
at least 200, at least 225, at least 250, at least 275, or at least
300 genes may be used for any evaluation described herein. As a
further set of non-limiting examples, up to four, up to five, up to
six, up to seven, up to eight, up to nine, up to ten, up to eleven,
up to twelve, up to 13, up to 14, up to 15, up to 16, up to 17, up
to 18, up to 19, up to 20, up to 21, up to 22, up to 23, up to 24,
up to 25, up to 26, up to 27, up to 28, up to 29, up to 30, up to
40, up to 50, up to 60, up to 70, up to 80, up to 90, up to 100, up
to 125, up to 150, up to 175, up to 200, up to 225, up to 250, up
to 275, or up to 300 genes may be used for any evaluation described
herein.
[0120] Any method may be used on a sample from a subject in order
to acquire expression data (e.g., indicating expression levels) for
the plurality of genes. As a set of non-limiting examples, the
expression data may be RNA expression data, DNA expression data, or
protein expression data.
[0121] DNA expression data, in some embodiments, refers to a level
of DNA in a sample from a subject. The level of DNA in a sample
from a subject having cancer may be elevated compared to the level
of DNA in a sample from a subject not having cancer, e.g., a gene
duplication in a cancer patient's sample. The level of DNA in a
sample from a subject having cancer may be reduced compared to the
level of DNA in a sample from a subject not having cancer, e.g., a
gene deletion in a cancer patient's sample.
[0122] DNA expression data, in some embodiments, refers to data for
DNA (or gene) expressed in a sample, for example, sequencing data
for a gene that is expressed in a patient's sample. Such data may
be useful, in some embodiments, to determine whether the patient
has one or more mutations associated with a particular cancer.
[0123] RNA expression data may be acquired using any method known
in the art including, but not limited to: whole transcriptome
sequencing, total RNA sequencing, mRNA sequencing, targeted RNA
sequencing, small RNA sequencing, ribosome profiling, RNA exome
capture sequencing, and/or deep RNA sequencing. DNA expression data
may be acquired using any method known in the art including any
known method of DNA sequencing. For example, DNA sequencing may be
used to identify one or more mutations in the DNA of a subject. Any
technique used in the art to sequence DNA may be used with the
methods and systems described herein. As a set of non-limiting
examples, the DNA may be sequenced through single-molecule
real-time sequencing, ion torrent sequencing, pyrosequencing,
sequencing by synthesis, sequencing by ligation (SOLiD sequencing),
nanopore sequencing, or Sanger sequencing (chain termination
sequencing). Protein expression data may be acquired using any
method known in the art including, but not limited to: N-terminal
amino acid analysis, C-terminal amino acid analysis, Edman
degradation (including though use of a machine such as a protein
sequenator), or mass spectrometry.
[0124] In some embodiments, the expression data comprises whole
exome sequencing (WES) data. In some embodiments, the expression
data comprises whole genome sequencing (WGS) data. In some
embodiments, the expression data comprises next-generation
sequencing (NGS) data. In some embodiments, the expression data
comprises microarray data.
Datasets
[0125] Any dataset containing information associated with a
biomarker may be used to obtain biomarker information as described
herein. In some embodiments, biomarker information may be obtained
from one or more databases and/or any other suitable electronic
repository of data. Examples of databases include, but are not
limited to, CGP (Cancer Genome Project), CPTAC (Clinical Proteomic
Tumor Analysis Consortium), ICGC (International Cancer Genome
Consortium), and TCGA (The Cancer Genome Atlas). In some
embodiments, biomarker information may be obtained from data
associated with a clinical trial. In some embodiments, biomarker
information may be predicted in association with a clinical trial
based on one or more similar drugs (e.g., drugs of a similar class
such as PD-1 inhibitors). In some embodiments, biomarker
information may be obtained from a hospital database. In some
embodiments, biomarker information may be obtained from a
commercial sequencing supplier. In some embodiments, biomarker
information may be obtained from a subject (e.g., a patient) and/or
a subject's (e.g., a patient's) relative, guardian, or
caretaker.
Assays
[0126] Any of the biological samples described herein can be used
for obtaining expression data using conventional assays or those
described herein. Expression data, in some embodiments, includes
gene expression levels. Gene expression levels may be detected by
detecting a product of gene expression such as mRNA and/or
protein.
[0127] In some embodiments, gene expression levels are determined
by detecting a level of a protein in a sample and/or by detecting a
level of activity of a protein in a sample. As used herein, the
terms "determining" or "detecting" may include assessing the
presence, absence, quantity and/or amount (which can be an
effective amount) of a substance within a sample, including the
derivation of qualitative or quantitative concentration levels of
such substances, or otherwise evaluating the values and/or
categorization of such substances in a sample from a subject.
[0128] The level of a protein may be measured using an immunoassay.
Examples of immunoassays include any known assay (without
limitation), and may include any of the following: immunoblotting
assay (e.g., Western blot), immunohistochemical analysis, flow
cytometry assay, immunofluorescence assay (IF), enzyme linked
immunosorbent assays (ELISAs) (e.g., sandwich ELISAs),
radioimmunoassays, electrochemiluminescence-based detection assays,
magnetic immunoassays, lateral flow assays, and related techniques.
Additional suitable immunoassays for detecting a level of a protein
provided herein will be apparent to those of skill in the art.
[0129] Such immunoassays may involve the use of an agent (e.g., an
antibody) specific to the target protein. An agent such as an
antibody that "specifically binds" to a target protein is a term
well understood in the art, and methods to determine such specific
binding are also well known in the art. An antibody is said to
exhibit "specific binding" if it reacts or associates more
frequently, more rapidly, with greater duration and/or with greater
affinity with a particular target protein than it does with
alternative proteins. It is also understood by reading this
definition that, for example, an antibody that specifically binds
to a first target peptide may or may not specifically or
preferentially bind to a second target peptide. As such, "specific
binding" or "preferential binding" does not necessarily require
(although it can include) exclusive binding. Generally, but not
necessarily, reference to binding means preferential binding. In
some examples, an antibody that "specifically binds" to a target
peptide or an epitope thereof may not bind to other peptides or
other epitopes in the same antigen. In some embodiments, a sample
may be contacted, simultaneously or sequentially, with more than
one binding agent that binds different proteins (e.g., multiplexed
analysis).
[0130] As used herein, the term "antibody" refers to a protein that
includes at least one immunoglobulin variable domain or
immunoglobulin variable domain sequence. For example, an antibody
can include a heavy (H) chain variable region (abbreviated herein
as VH), and a light (L) chain variable region (abbreviated herein
as VL). In another example, an antibody includes two heavy (H)
chain variable regions and two light (L) chain variable regions.
The term "antibody" encompasses antigen-binding fragments of
antibodies (e.g., single chain antibodies, Fab and sFab fragments,
F(ab')2, Fd fragments, Fv fragments, scFv, and domain antibodies
(dAb) fragments (de Wildt et al., Eur J Immunol. 1996;
26(3):629-39.)) as well as complete antibodies. An antibody can
have the structural features of IgA, IgG, IgE, IgD, IgM (as well as
subtypes thereof). Antibodies may be from any source including, but
not limited to, primate (human and non-human primate) and
primatized (such as humanized) antibodies.
[0131] In some embodiments, the antibodies as described herein can
be conjugated to a detectable label and the binding of the
detection reagent to the peptide of interest can be determined
based on the intensity of the signal released from the detectable
label. Alternatively, a secondary antibody specific to the
detection reagent can be used. One or more antibodies may be
coupled to a detectable label. Any suitable label known in the art
can be used in the assay methods described herein. In some
embodiments, a detectable label comprises a fluorophore. As used
herein, the term "fluorophore" (also referred to as "fluorescent
label" or "fluorescent dye") refers to moieties that absorb light
energy at a defined excitation wavelength and emit light energy at
a different wavelength. In some embodiments, a detection moiety is
or comprises an enzyme. In some embodiments, an enzyme is one
(e.g., .beta.-galactosidase) that produces a colored product from a
colorless substrate.
[0132] It will be apparent to those of skill in the art that this
disclosure is not limited to immunoassays. Detection assays that
are not based on an antibody, such as mass spectrometry, are also
useful for the detection and/or quantification of a protein and/or
a level of protein as provided herein. Assays that rely on a
chromogenic substrate can also be useful for the detection and/or
quantification of a protein and/or a level of protein as provided
herein.
[0133] Alternatively, the level of nucleic acids encoding a gene in
a sample can be measured via a conventional method. In some
embodiments, measuring the expression level of nucleic acid
encoding the gene comprises measuring mRNA. In some embodiments,
the expression level of mRNA encoding a gene can be measured using
real-time reverse transcriptase (RT) Q-PCR or a nucleic acid
microarray. Methods to detect nucleic acid sequences include, but
are not limited to, polymerase chain reaction (PCR), reverse
transcriptase-PCR (RT-PCR), in situ PCR, quantitative PCR (Q-PCR),
real-time quantitative PCR (RT Q-PCR), in situ hybridization,
Southern blot, Northern blot, sequence analysis, microarray
analysis, detection of a reporter gene, or other DNA/RNA
hybridization platforms.
[0134] In some embodiments, the level of nucleic acids encoding a
gene in a sample can be measured via a hybridization assay. In some
embodiments, the hybridization assay comprises at least one binding
partner. In some embodiments, the hybridization assay comprises at
least one oligonucleotide binding partner. In some embodiments, the
hybridization assay comprises at least one labeled oligonucleotide
binding partner. In some embodiments, the hybridization assay
comprises at least one pair of oligonucleotide binding partners. In
some embodiments, the hybridization assay comprises at least one
pair of labeled oligonucleotide binding partners.
[0135] Any binding agent that specifically binds to a desired
nucleic acid or protein may be used in the methods and kits
described herein to measure an expression level in a sample. In
some embodiments, the binding agent is an antibody or an aptamer
that specifically binds to a desired protein. In other embodiments,
the binding agent may be one or more oligonucleotides complementary
to a nucleic acid or a portion thereof. In some embodiments, a
sample may be contacted, simultaneously or sequentially, with more
than one binding agent that binds different proteins or different
nucleic acids (e.g., multiplexed analysis).
[0136] To measure an expression level of a protein or nucleic acid,
a sample can be in contact with a binding agent under suitable
conditions. In general, the term "contact" refers to an exposure of
the binding agent with the sample or cells collected therefrom for
suitable period sufficient for the formation of complexes between
the binding agent and the target protein or target nucleic acid in
the sample, if any. In some embodiments, the contacting is
performed by capillary action in which a sample is moved across a
surface of the support membrane.
[0137] In some embodiments, an assay may be performed in a
low-throughput platform, including single assay format. In some
embodiments, an assay may be performed in a high-throughput
platform. Such high-throughput assays may comprise using a binding
agent immobilized to a solid support (e.g., one or more chips).
Methods for immobilizing a binding agent will depend on factors
such as the nature of the binding agent and the material of the
solid support and may require particular buffers. Such methods will
be evident to one of ordinary skill in the art.
Genes
[0138] The various genes recited herein are, in general, named
using human gene naming conventions. The various genes, in some
embodiments, are described in publically available resources such
as published journal articles. The gene names may be correlated
with additional information (including sequence information)
through use of, for example, the NCBI GenBank.RTM. databases
available at www <dot> ncbi <dot> nlm <dot> nih
<dot> gov; the HUGO (Human Genome Organization) Gene
Nomination Committee (HGNC) databases available at www <dot>
genenames <dot> org; the DAVID Bioinformatics Resource
available at www <dot> david <dot> ncifcrf <dot>
gov. It should be appreciated that a gene may encompass all
variants of that gene. For organisms or subjects other than human
subjects, corresponding specific-specific genes may be used.
Synonyms, equivalents, and closely related genes (including genes
from other organisms) may be identified using similar databases
including the NCBI GenBank.RTM. databases described above.
[0139] In some embodiments, gene AXL may be identified as
GenBank.RTM. Accession number NM_199054.2 or NM_017572.3; gene CCL2
may be identified as GenBank.RTM. Accession number NM_002982.3;
gene CCL7 may be identified as GenBank.RTM. Accession number
NM_006273.3; gene CCL8 may be identified as GenBank.RTM. Accession
number NM_005623.2; gene CDH1 may be identified as GenBank.RTM.
Accession number NM_004360.4, NM_001317184.1, NM_001317185.1, or
NM_001317186.1; gene VEGFC may be identified as GenBank.RTM.
Accession number NM_005429.4; gene EGFR may be identified as
GenBank.RTM. Accession number NM_001346941.1, NM_005228.4,
NM_001346898.1, NM_001346900.1, NM_001346899.1, NM_001346897.1,
NM_201284.1, NM_201283.1 or NM_201282.1; gene ROR2 may be
identified as GenBank.RTM. Accession number NM_004560.3 or
NM_001318204.1; gene PTEN may be identified as GenBank.RTM.
Accession number NM_001304717.2, NM_000314.6 or NM_001304718.1;
gene TAGLN may be identified as GenBank.RTM. Accession number
NM_001001522.2 or NM_003186.4.
Predicting Therapy Response
[0140] Normalized biomarker scores derived from a patient and/or a
patient's biological sample as described herein may be used for
various clinical purposes including, for example, identifying
subjects suitable for a particular treatment (e.g., an
immunotherapy), and/or predicting likelihood of a patient's
response or lack thereof to a particular treatment. Accordingly,
described herein are prognostic methods for predicting therapy
efficacy, for example, an immunotherapy, based on a patient's
biomarker values. Additionally, the systems and methods described
herein may be used to predict whether a patient (subject) may or
may not have one or more adverse reactions to a particular therapy,
based on the patient's biomarker values (e.g., whether a subject is
likely to have immune-mediated adverse reactions to checkpoint
blockade therapy and/or not have immune-mediated adverse reactions
to checkpoint blockade therapy).
[0141] To practice methods for predicting therapeutic efficacy as
described herein, a therapy score for a patient may be determined
for a particular therapy. As used herein, the term "therapy score"
is calculated using multiple normalized biomarker scores for a
patient that is indicative of a predicted response of that subject
to a therapy. As a set of non-limiting examples, such a "therapy
score" may be calculated using multiple normalized biomarker scores
in one or more of the following ways: 1) as a sum; 2) as a weighted
sum (e.g., in a regression model); 3) using any linear or
generalized linear model taking the normalized biomarker scores as
inputs and producing, based on the input normalized biomarker
scores, an output indicative of a patient's predicted response to a
therapy; 4) using any statistical model (e.g., a neural network
model, a Bayesian regression model, an adaptive non-linear
regression model, a support vector regression model, a Gaussian
mixture model, random forest regression, and/or any other suitable
type mixture model) taking the normalized biomarker scores as
inputs and producing, based on the input biomarker scores, an
output indicative of a patient's predicted response to a
therapy.
[0142] A therapy score as described herein includes a therapy score
calculated using any suitable number of normalized biomarker
scores. In some embodiments, the therapy score may be calculated
using at least 2 normalized biomarker scores. In some embodiments,
the therapy score may be calculated using at least 3, at least 4,
at least 5, at least 6, at least 7, at least 8, at least 9, at
least 10, at least 20, at least 30, at least 40, at least 50, at
least 60, at least 70, at least 80, at least 90, or at least 100
normalized biomarker scores.
[0143] In some embodiments, a therapy score is calculated using one
or more normalized biomarker values which may be weighted by one or
more respective weights as part of the calculation. A biomarker
weight may be assigned to any biomarker. For example, an abundant
biomarker may be assigned a higher weight for predicting a therapy
response. Such weights may be determined, for example, using a
machine learning technique. As a non-limiting set of examples, such
weights may be determined by training a regression model (e.g., a
linear regression model, a generalized linear model, a support
vector regression model, a logistic regression model, a random
forest regression model, a neural network model, etc.).
[0144] A therapy score for a therapy may be a positive value or a
negative value. A positive therapy score, in some embodiments, is
indicative of a positive response to a therapy. A negative therapy
score, in some embodiments, is indicative of a negative response or
no response to a therapy. A therapy score close to zero, in some
embodiments, is indicative of little or no measurable response to a
therapy.
[0145] A therapy score, in some embodiments, more accurately
predicts a patient's response to a therapy when compared, for
example, to using a single biomarker. For example, a patient's
response to a therapy may be more accurately predicted as a therapy
score positively increases in numeric value. In another example, a
patient's lack of response to a therapy may be more accurately
predicted as a therapy score negatively increases in numeric
value.
[0146] The terms "subject" or "patient" may be used interchangeably
and refer to a subject who needs the analysis as described herein.
In some embodiments, the subject is a human or a non-human mammal
(e.g., a non-human primate). In some embodiments, the subject is
suspected to have cancer or is at risk for cancer. In some
embodiments, the subject has (e.g., is known to have) cancer.
Examples of cancer include, without limitation, adrenocortical
carcinoma, bladder urothelial carcinoma, breast invasive carcinoma,
cervical squamous cell carcinoma, endocervical adenocarcinoma,
colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell
carcinoma, kidney renal papillary cell carcinoma, liver
hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell
carcinoma, ovarian serous cystadenocarcinoma, pancreatic
adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma,
skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma,
uterine corpus endometrial carcinoma, one or more types of
leukemia, and cholangiocarcinoma.
[0147] In some embodiments, the subject is a human patient having
one or more symptom of a cancer. For example, the subject may have
fatigue, pain, weakness or numbness, loss of bladder or bowl
control, cough, blood-tinged saliva, anemia, breast lump or
discharge, or a combination thereof. In some embodiments, the
subject has a symptom of cancer or has a history of a symptom of
cancer. In some embodiments, the subject has more than one symptom
of cancer or has a history of more than one symptoms of cancer. In
some embodiments, the subject has no symptom of cancer, has no
history of a symptom of cancer, or has no history of cancer.
[0148] Such a subject may exhibit one or more symptoms associated
with a cancer. Alternatively or in addition, such a subject may
have one or more risk factors for cancer, for example, an
environmental factor associated with cancer (e.g., geographic
location or exposure to a mutagen), a family history of cancer,
and/or a genetic predisposition to developing cancer.
[0149] Alternatively, the subject who needs the analysis described
herein may be a patient having cancer or suspected of having
cancer. Such a subject may currently be having a relapse, or may
have suffered from the disease in the past (e.g., may be currently
relapse-free), or may have cancer. In some examples, the subject is
a human patient who may be on a treatment (i.e., the subject may be
receiving treatment) for the disease including, for example, a
treatment involving chemotherapy or radiation therapy. In other
instances, such a human patient may be free of such a
treatment.
Impact Scores
[0150] In some embodiments, the systems and methods described
herein may be used to assess the effectiveness of a therapy over
time. In some embodiments, aspects of the disclosure provide
methods and systems for using normalized biomarker scores obtained
from samples prior to and subsequent to administration of a
candidate therapy to determine the efficacy of that therapy. In
some embodiments, such methods may also be used to select a
candidate therapy for use with a patient or subject. In certain
embodiments, such methods may be used to assess the impact of a
candidate therapy, which impact may be quantified by determining an
impact score, in accordance with some embodiments described
herein.
[0151] For example, some embodiments provide for determining, using
a first and second set of normalized biomarker scores for a
subject, an impact score for a candidate therapy, wherein the first
and second set of normalized biomarker scores are determined using
first sequencing data about at least one biological sample of a
subject prior to administration of the candidate therapy, and
second sequencing data about at least one biological sample of a
subject subsequent to administration of the candidate therapy. Such
an impact score would be indicative of response (e.g., a positive
or negative response) of the subject to administration of the
candidate therapy.
Computer Implemented Methods for Predicting or Describing Therapy
Response
[0152] Aspects of the disclosure provide computer implemented
methods for determining, using a set of normalized biomarker
scores, biomarker scores for a subject indicative of a patient's
response or lack thereof to a particular therapy.
[0153] In some embodiments, a software program may provide a user
with a visual representation presenting information related to a
patient's biomarkers scores (e.g., a biomarker score, and/or a
therapy score, and/or an impact score), and predicted efficacy of a
therapy. Such a software program may execute in any suitable
computing environment including, but not limited to, a
cloud-computing environment, a device co-located with a user (e.g.,
the user's laptop, desktop, smartphone, etc.), one or more devices
remote from the user (e.g., one or more servers), etc.
[0154] For example, in some embodiments, the techniques described
herein may be implemented in the illustrative environment 100 shown
in FIG. 1A. As shown in FIG. 1A, within illustrative environment
100, one or more biological samples of a patient 102 may be
provided to a laboratory 104. Laboratory 104 may process the
biological sample(s) to obtain sequencing data (e.g.,
transcriptome, exome, and/or genome sequencing data) and provide
it, via network 108, to at least one database 106 that stores
information about patient 102.
[0155] Network 108 may be a wide area network (e.g., the Internet),
a local area network (e.g., a corporate Intranet), and/or any other
suitable type of network. Any of the devices shown in FIG. 1A may
connect to the network 108 using one or more wired links, one or
more wireless links, and/or any suitable combination thereof.
[0156] In the illustrated embodiment of FIG. 1A, the at least one
database 106 may store sequencing data for the patient, expression
data for the patient, medical history data for the patient, test
result data for the patient, and/or any other suitable information
about the patient 102. Examples of stored test result data for the
patient include biopsy test results, imaging test results (e.g.,
MRI results), and blood test results. The information stored in at
least one database 106 may be stored in any suitable format and/or
using any suitable data structure(s), as aspects of the technology
described herein are not limited in this respect. The at least one
database 106 may store data in any suitable way (e.g., one or more
databases, one or more files). The at least one database 106 may be
a single database or multiple databases.
[0157] As shown in FIG. 1A, illustrative environment 100 includes
one or more external databases 116, which may store information for
patients other than patient 102. For example, external databases
116 may store expression data (of any suitable type) for one or
more patients, medical history data for one or more patients, test
result data (e.g., imaging results, biopsy results, blood test
results) for one or more patients, demographic and/or biographic
information for one or more patients, and/or any other suitable
type of information. In some embodiments, external database(s) 116
may store information available in one or more publically
accessible databases such as TCGA (The Cancer Genome Atlas), one or
more databases of clinical trial information, and/or one or more
databases maintained by commercial sequencing suppliers. The
external database(s) 116 may store such information in any suitable
way using any suitable hardware, as aspects of the technology
described herein are not limited in this respect.
[0158] In some embodiments, the at least one database 106 and the
external database(s) 116 may be the same database, may be part of
the same database system, or may be physically co-located, as
aspects of the technology described herein are not limited in this
respect.
[0159] In some embodiments, information stored in patient
information database 106 and/or in external database(s) 116 may be
used to perform any of the techniques described herein related to
determining a therapy score and/or impact score indicative of a
patient's response to a therapy. For example, the information
stored in the database(s) 106 and/or 116 may be accessed, via
network 108, by software executing on server(s) 110 to perform any
one or more of the techniques described herein in connection with
FIGS. 2A, 2B, 2C, 2D and 2E.
[0160] For example, in some embodiments, server(s) 110 may access
information stored in database(s) 106 and/or 116 and use this
information to perform process 200, described with reference to
FIG. 2A, for determining therapy scores for multiple therapies
based on normalized biomarker scores.
[0161] As another example, server(s) 110 may access information
stored in database(s) 106 and/or 116 and use this information to
perform process 220, described with reference to FIG. 2B, for
determining the effectiveness of a candidate therapy on a
patient.
[0162] As another example, server(s) 110 may access information
stored in database(s) 106 and/or 116 and use this information to
perform process 240, described with reference to FIG. 2C, for
determining therapy scores for at least two selected therapies
based on normalized biomarker scores for at least three biomarkers
for each of the therapies.
[0163] As another example, server(s) 110 may access information
stored in database(s) 106 and/or 116 and use this information to
perform process 260, described with reference to FIG. 2D, for
obtaining first and second therapy scores for first and second
therapies.
[0164] As yet another example, server(s) 110 may access information
stored in database(s) 106 and/or 116 and use this information to
perform process 280, described with reference to FIG. 2E, for
identifying a subject as a member of a cohort using normalized
biomarker scores.
[0165] In some embodiments, server(s) 110 may include one or
multiple computing devices. When server(s) 110 include multiple
computing devices, the device(s) may be physically co-located
(e.g., in a single room) or distributed across multi-physical
locations. In some embodiments, server(s) 110 may be part of a
cloud computing infrastructure. In some embodiments, one or more
server(s) 110 may be co-located in a facility operated by an entity
(e.g., a hospital, research institution) with which doctor 114 is
affiliated. In such embodiments, it may be easier to allow
server(s) 110 to access private medical data for the patient
102.
[0166] As shown in FIG. 1A, in some embodiments, the results of the
analysis performed by server(s) 110 may be provided to doctor 114
through a computing device 114 (which may be a portable computing
device, such as a laptop or smartphone, or a fixed computing device
such as a desktop computer). The results may be provided in a
written report, an e-mail, a graphical user interface, and/or any
other suitable way. It should be appreciated that although in the
embodiment of FIG. 1A, the results are provided to a doctor, in
other embodiments, the results of the analysis may be provided to
patient 102 or a caretaker of patient 102, a healthcare provider
such as a nurse, or a person involved with a clinical trial.
[0167] In some embodiments, the results may be part of a graphical
user interface (GUI) presented to the doctor 114 via the computing
device 112. In some embodiments, the GUI may be presented to the
user as part of a webpage displayed by a web browser executing on
the computing device 112. In some embodiments, the GUI may be
presented to the user using an application program (different from
a web-browser) executing on the computing device 112. For example,
in some embodiments, the computing device 112 may be a mobile
device (e.g., a smartphone) and the GUI may be presented to the
user via an application program (e.g., "an app") executing on the
mobile device.
[0168] The GUI presented on computing device 112 provides a wide
range of oncological data relating to both the patient and the
patient's cancer in a new way that is compact and highly
informative. Previously, oncological data was obtained from
multiple sources of data and at multiple times making the process
of obtaining such information costly from both a time and financial
perspective. Using the techniques and graphical user interfaces
illustrated herein, a user can access the same amount of
information at once with less demand on the user and with less
demand on the computing resources needed to provide such
information. Low demand on the user serves to reduce clinician
errors associated with searching various sources of information.
Low demand on the computing resources serves to reduce processor
power, network bandwidth, and memory needed to provide a wide range
of oncological data, which is an improvement in computing
technology.
[0169] FIG. 1B shows a block diagram of an illustrative GUI 150
containing information about patient 102. GUI 150 may include
separate portions providing different types of information about
patient 102. Illustrative GUI 150 includes the following portions:
Patient Information Portion 152, Molecular-Functional (MF) Portrait
Portion 160, Clinical Trial Information Portion 162, Immunotherapy
Portion 154, Efficacy Predictor Portion 156, and Targeted Therapy
Selection Portion 158.
[0170] Patient Information Portion 152 may provide general
information about the patient and the patient's cancer. General
information about the patient may include such information as the
patient's name and date of birth, the patient's insurance provider,
and contact information for the patient such as address and phone
number. General information about the patient's cancer may include
the patient's diagnosis, the patient's history of relapse and/or
remission, and information relating to stage of the patient's
cancer. Patient Information Portion 152 may also provide
information relating to potential treatment options for the patient
and/or previously administered treatments.
[0171] Molecular-Functional (MF) Portrait Portion 160 may include a
molecular functional tumor portrait (MF profile) which refers to a
graphical depiction of a tumor with regard to its molecular and
cellular composition, and biological processes that are present
within and/or surrounding the tumor. Further aspects relating to a
patient's MF profile are provided in International patent
application number PCT/US18/37017, entitled "Systems and Methods
for Generating, Visualizing and Classifying Molecular Functional
Profiles," filed Jun. 12, 2018, the entire contents of which are
incorporated herein by reference.
[0172] Clinical Trial Information Portion 162 may include
information relating to a clinical trial for a therapy that may be
and/or will be administered to the patient. Clinical Trial
Information Portion 162 may provide information about an ongoing
clinical trial or a completed clinical trial. Information that may
be provided in Clinical Trial Information Portion 162 may include
information related to a therapy used in the clinical trial such as
dosage and dosage regimen, number and diagnosis of patients
participating in the clinical trial, and patient outcomes.
[0173] Immunotherapy Portion 154 may include patient specific
information as it relates to an immunotherapy. Immunotherapy
Portion 154 may provide such information for different
immunotherapies, for example, immune checkpoint blockade therapies,
anti-cancer vaccine therapies, and T cell therapies. Patient
specific information relating to an immunotherapy may include
information about the patient such as the patient's biomarkers
associated with an immunotherapy and/or information about the
patient's cancer such as composition of immune cells in the
patient's tumor.
[0174] Efficacy Predictor Portion 156 may include information
indicative of the patient's predicted response to an immunotherapy
based on patient specific information presented in Immunotherapy
Portion 154. Efficacy Predictor Portion 156 may provide predicted
efficacy of an immunotherapy determined, in some embodiments, using
a patient's biomarkers as described in herein. Additionally or
alternatively, Efficacy Predictor Portion 156 may provide predicted
efficacy of an immune checkpoint blockade therapy determined using
patient specific information such as gene expression data as
described in International patent application number
PCT/US18/37018, entitled "Systems and Methods for Identifying
Responders and Non-Responders to Immune Checkpoint Blockade
Therapy," filed Jun. 12, 2018, the entire contents of which are
incorporated herein by reference.
[0175] Targeted Therapy Selection Portion 158 may include patient
specific information as it relates to a targeted therapy. Targeted
Therapy Selection Portion 158 may provide such information for
different targeted therapies, for example, a kinase inhibitor
therapy, a chemotherapy, and anti-cancer antibody therapy. Patient
specific information relating to an a targeted therapy may include
information about the patient such as the patient's biomarkers
associated with a targeted therapy and/or information about the
patient's cancer such as whether a mutation is present in the
patient's tumor.
[0176] An illustrative example of the graphical user interface 150
of FIG. 1B is shown as graphical user interface 170 of FIG. 1C. As
shown in FIG. 1C, Patient Information Portion 172 may provide
different information in different panels, for example, Overall
Status panel, Disease Characteristics panel, and General
Recommendations panel. Overall Status panel, in some embodiments,
may provide general information about the patient such as patient
name and patient age. Disease Characteristics panel, in some
embodiments, may provide information about the patient's cancer
such as type of cancer and stage of cancer. General Recommendations
panel, in some embodiments, may provide previous treatments and
possible treatment options for the patient.
[0177] Clinical Trial Information Portion 182a provides information
relating to a clinical trial for anti-PD1 therapy. Clinical Trial
Information Portion 182a (as shown in the upper portion) shows a
graph providing patient overall response rate (ORR) for anti-PD1
therapy and other therapies such as vaccine or IFN.alpha.
therapies. A user may select portions of the Clinical Trial
Information Portion 182a to access information related to patient
progression-free survival (PFS) and/or patient overall survival
(OS). Clinical Trial Information Portion 182a (as shown in the
lower portion) provides information relating to different clinical
trials that may be presented to a user including a brief
description of the clinical trial.
[0178] Clinical Trial Information Portion 182b provides information
relating to a clinical trial for different targeted therapies.
Clinical Trial Information Portion 182b (as shown in the upper
portion) shows a graph providing patient overall response rate
(ORR) for different targeted therapies including sunitinib (SU),
imatinib (IM), vemurafenib (VER) and dabrafenib (DAB). A user may
select portions of the Clinical Trial Information Portion 182b to
access information related to patient progression-free survival
(PFS) and/or patient overall survival (OS). Clinical Trial
Information Portion 182b (as shown in the lower portion) provides
information relating to different clinical trials that may be
presented to a user including a brief description of the clinical
trial.
[0179] Immunotherapy Portion 174 provides patient specific
information associated with an immunotherapy and information
indicative of the patient's predicted response to that
immunotherapy. Immunotherapy Portion 174 provides such information
for anti-PD1 therapy, a therapeutic cancer vaccine, IFN.alpha.
therapy, IL2 therapy, anti-CTLA4 therapy, and anti-angiogenic
therapy. Patient specific information shown in Immunotherapy
Portion 174 includes the patient's biomarker information relating
to various immunotherapies and the patient's therapy scores
calculated from their biomarkers.
[0180] Efficacy Predictor Portion 176a provides information
indicative of the patient's predicted response to anti-PD1 therapy
based on patient specific information presented in Immunotherapy
Portion 174. Efficacy Predictor Portion 176b provides information
indicative of the patient's predicted response to anti-CTLA4
therapy based on patient specific information presented in
Immunotherapy Portion 174.
[0181] Targeted Therapy Selection Portion 178 provides patient
specific information associated with a targeted therapy and
information indicative of the patient's predicted response to the
targeted therapy. Targeted Therapy Selection Portion 178 provides
such information for sunitinib (SU), imatinib (IM), vemurafenib
(VER), dabrafenib (DAB), trametinib, and pazopanib. Patient
specific information shown in Targeted Therapy Selection Portion
178 includes a patient's biomarker information relating to various
targeted therapies and the patient's therapy scores calculated from
their biomarkers.
[0182] An illustrative implementation of a computer system 1500
that may be used in connection with any of the embodiments of the
technology described herein is shown in FIG. 15. The computer
system 1500 may include one or more computer hardware processors
1510 and one or more articles of manufacture that comprise
non-transitory computer-readable storage media (e.g., memory 1520
and one or more non-volatile storage devices 1530). The
processor(s) 1510 may control writing data to and reading data from
the memory 1520 and the non-volatile storage device(s) 1530 in any
suitable manner. To perform any of the functionality described
herein, the processor(s) 1510 may execute one or more
processor-executable instructions stored in one or more
non-transitory computer-readable storage media (e.g., the memory
1520), which may serve as non-transitory computer-readable storage
media storing processor-executable instructions for execution by
the processor(s) 1510.
[0183] FIG. 2A is a flowchart of an illustrative
computer-implemented process 200 for determining therapy scores for
multiple therapies based on normalized biomarker scores, in
accordance with some embodiments of the technology described
herein. A therapy score provided herein may be indicative of a
patient's response to a particular therapy based on the patient's
normalized biomarker scores for biomarkers associated with the
particular therapy. Process 200 may be performed by any suitable
computing device(s). For example, process 200 may be performed by a
laptop computer, a desktop computer, one or more servers, in a
cloud computing environment, or in any other suitable way.
[0184] Process 200 begins at act 202, where sequencing data for a
subject is obtained. Any type of sequencing data may be obtained,
for example, sequencing data from transcriptome, exome, and/or
genome sequencing of a patient's tumor biopsy. In some embodiments,
obtaining sequencing data comprises obtaining sequencing data from
a biological sample obtained from the subject and/or from a
database storing such information. Further aspects relating to
obtaining sequencing data are provided in section "Sample Analysis"
and "Obtaining Biomarker Information".
[0185] Next, process 200 proceeds to act 204, where biomarker
information indicating distribution of values for biomarkers
associated with multiple therapies is accessed. In some
embodiments, for each particular one of multiple therapies,
information indicating a respective distribution of values (in a
reference population) for each one of one or more biomarkers
associated with the particular therapy may be accessed. Such
biomarker information may be obtained from one or more databases,
in some embodiments.
[0186] Next, process 200 proceeds to act 206, where normalized
biomarker scores for the subject are determined using sequencing
data obtained at act 202 and the biomarker information obtained at
act 204. Normalized biomarker scores for the subject are
determined, in some embodiments, using a reference subset of
biomarkers comprising any number of biomarkers from any number of
reference subjects. In that way, the subject's biomarker score is
adjusted (e.g., normalized) to a common scale based on a
distribution of biomarker values in a reference subset of
biomarkers. Further aspects relating to determining normalized
biomarker scores are provided in section "From Biomarker Values To
Normalized Biomarker Scores".
[0187] Next, process 200 proceeds to act 208, where therapy scores
for each particular one of the multiple therapies are determined
based on normalized biomarker scores for the biomarkers associated
with the each particular one therapy. A therapy score may be
calculated using multiple normalized biomarker scores as a sum, as
a weighted sum, using a linear or generalized linear model, using a
statistical model, or combinations thereof. The therapy score may
be calculated using any suitable number of normalized biomarker
scores, e.g., 2, 10, 50, or 100 normalized biomarker scores.
Further aspects relating to determining therapy scores are provided
in section "Predicting Therapy Response".
[0188] Therapy scores for any number of therapies may be output to
a user, in some embodiments, by displaying the information to the
user in a graphical user interface (GUI), including the information
in a report, sending an email to the user, and/or in any other
suitable way. For example, therapy scores and other patient related
information may be provided to a user in a GUI as shown in FIGS.
9-14.
[0189] Systems and methods described herein may be used to assess
the effectiveness of a therapy over time. Such systems and methods
involve determining an impact score for a candidate therapy
indicative of an impact of the candidate therapy on the patient
based on the patient's biomarker information obtained prior to and
subsequent to administration of the candidate therapy.
[0190] FIG. 2B is a flowchart of an illustrative
computer-implemented process 220 for determining an impact score
for a candidate therapy using first and second normalized biomarker
scores, in accordance with some embodiments of the technology
described herein. An impact score provided herein is indicative of
a patient's response to a candidate therapy over time based on the
patient's normalized biomarker scores obtained before, during
and/or after treatment. In some embodiments, a first normalized
biomarker score may be obtained before treatment and a second
normalized biomarker score may be obtained during and/or after
treatment.
[0191] Process 220 begins at act 222, where first sequencing data
for a subject prior to administration of a candidate therapy is
obtained. Sequencing data for a subject prior to treatment includes
any sequencing data obtained for that subject any amount of time
prior to treatment. Any type of sequencing data may be obtained,
for example, sequencing data from transcriptome, exome, and/or
genome sequencing of a patient's tumor biopsy. Sequencing data for
the subject may be obtained minutes, days, months, or years prior
to treatment. Further aspects relating to obtaining sequencing data
are provided in section "Sample Analysis".
[0192] Next, process 220 proceeds to act 224, where second
sequencing data for a subject subsequent to administration of a
candidate therapy is obtained. Sequencing data for a subject
subsequent to treatment includes any sequencing data obtained for
that subject any amount of time subsequent to treatment. Sequencing
data for the subject may be obtained minutes, days, months, or
years subsequent to treatment. The second sequencing data may be a
different type of sequencing data than the first sequencing data
obtained prior to treatment. Further aspects relating to obtaining
sequencing data are provided in section "Sample Analysis".
[0193] Next, process 220 proceeds to act 226, where biomarker
information indicating a distribution of values for each of
multiple biomarkers associated with the candidate therapy is
accessed. Accessing biomarker information includes obtaining
biomarker information associated with the candidate therapy from a
variety of sources including from one or more databases. Biomarker
information associated with the candidate therapy may be obtained
from a subject prior to administration of a therapy and/or after
administration of a therapy.
[0194] Next, process 220 proceeds to act 228, where first and
second normalized biomarker scores for the subject are determined
using first and second sequencing data and biomarker information.
First and second normalized biomarker scores for the subject are
determined, in some embodiments, using a reference subset of
biomarkers comprising sets of biomarker values for the same
biomarkers in multiple reference subjects. In that way, the
subject's first and second biomarker score is adjusted (e.g.,
normalized) to a common scale based on a distribution of biomarker
values in a reference subset of biomarkers. Further aspects
relating to determining normalized biomarker scores are provided in
section "From Biomarker Values To Normalized Biomarker Scores".
[0195] Next, process 220 proceeds to act 230, where an impact score
for the candidate therapy is determined based on first and second
normalized biomarker scores. Such impact scores, in some
embodiments, may be indicative of efficacy of the candidate
therapy. In some embodiments, impact scores may be used to select
an additional therapy, stop administration of an ongoing therapy,
and/or adjust how an ongoing therapy is being administered for the
patient. Further aspects relating to determining impact scores are
provided in section "Impact Scores".
[0196] Impact scores for any number and/or any type of candidate
therapies may be output to a user, in some embodiments, by
displaying the information to the user in a graphical user
interface (GUI), including the information in a report, sending an
email to the user, and/or in any other suitable way. For example,
impact scores and other patient related information may be provided
to a user in a GUI as shown in FIGS. 9-14.
[0197] Systems and methods described herein provide a multiple
biomarker analysis that provides a more accurate prediction of a
patient's response to therapy than that provided by a single
biomarker analysis.
[0198] FIG. 2C is a flowchart of an illustrative
computer-implemented process 240 for determining therapy scores for
at least two selected therapies based on respective normalized
biomarker scores for at least three biomarkers, in accordance with
some embodiments of the technology described herein. Therapy scores
may be determined for selected therapies of any suitable type. For
example, therapy scores may be determined for an immune checkpoint
blockade therapy (e.g., anti-PD1 therapy) and a kinase inhibitor
therapy (e.g., Sunitinib). In another example, therapy scores may
be determined for two different immune checkpoint blockade
therapies (e.g., anti-PD1 therapy and anti-CTLA4 therapy). Therapy
scores may also be determined using any type of three biomarkers.
For example, therapy scores may be determined from at least three
different genetic biomarkers or therapy scores may be determined
from a genetic biomarker, a cellular biomarker, and an expression
biomarker.
[0199] Process 240 begins at act 242, where sequencing data for a
subject is obtained. Any type of sequencing data may be obtained,
for example, sequencing data from transcriptome, exome, and/or
genome sequencing of a patient's tumor biopsy. In some embodiments,
obtaining sequencing data comprises obtaining sequencing data from
a biological sample obtained from the subject and/or from a
database storing such information. Further aspects relating to
obtaining sequencing data are provided in section "Sample
Analysis".
[0200] Next, process 240 proceeds to act 244, where biomarker
information indicating distribution of values for the at least
three biomarkers associated with the at least two therapies is
accessed. For each therapy, information indicating a distribution
of values for each of at least three biomarkers associated with
each particular therapy may be accessed. Thus, in some embodiments,
at least six distributions of values may be accessed (e.g., at
least three biomarker value distributions for three biomarkers
associated with a first selected therapy and at least three
biomarker value distributions for three biomarkers associated with
a second selected therapy). Accessing biomarker information may
include obtaining biomarker information from a variety of sources
including one or more databases.
[0201] Next, process 240 proceeds to act 246, where first and
second sets of normalized biomarker scores for the subject are
determined using the sequencing data obtained at act 242 and
biomarker information obtained at act 244. First and second sets of
normalized biomarker scores for the subject are determined, in some
embodiments, using a reference subset of biomarkers comprising sets
of biomarker values for the same biomarkers in multiple reference
subjects. In that way, the subject's first and second sets of
biomarker scores are adjusted (e.g., normalized) to a common scale
based on a distribution of biomarker values in a reference subset
of biomarkers. Since the first set of biomarkers is associated with
one therapy and the second set of biomarkers is associated with
another therapy, the first and second sets of normalized biomarkers
may differ from each other, for example, in number of biomarkers
and/or types of biomarkers. For example, the first set of
normalized biomarker scores may be associated with a first therapy
and the second set of normalized biomarker scores may be associated
with a second therapy. Further aspects relating to determining
normalized biomarker scores are provided in section "From Biomarker
Values To Normalized Biomarker Scores". Next, process 240 proceeds
to act 248, where therapy scores for the at least two therapies are
determined based on at least three normalized biomarker scores for
each therapy. A therapy score may be calculated using the at least
three normalized biomarker scores as a sum, as a weighted sum,
using a linear or generalized linear model, using a statistical
model, or combinations thereof. The therapy score may be calculated
using any suitable number of normalized biomarker scores, e.g., 2,
10, 50, or 100 normalized biomarker scores. Further aspects
relating to determining therapy scores are provided in section
"Predicting Therapy Response".
[0202] Therapy scores for the at least two therapies and/or
biomarker information used for determining therapy scores may be
output to a user, in some embodiments, by displaying the
information to the user in a graphical user interface (GUI),
including the information in a report, sending an email to the
user, and/or in any other suitable way. For example, therapy scores
and other patient related information may be provided to a user in
a GUI as shown in FIGS. 9-14.
[0203] Systems and methods described herein provide for determining
more than one therapy score for a particular therapy. For example,
a first and a second therapy score may be determined for a first
therapy, and a first and second therapy score may be determined for
a second therapy.
[0204] FIG. 2D is a flowchart of an illustrative
computer-implemented process 260 for determining first and second
therapy scores for a first and second therapy, respectively, based
on normalized biomarker scores, in accordance with some embodiments
of the technology described herein. First and second therapy scores
may be determined using different biomarkers or different
combinations of biomarkers. For example, a first therapy score is
determined based on a patient's genetic biomarkers and a second
therapy score is based on the patient's expression biomarkers. In
another example, a first therapy score is determined based on a
patient's genetic biomarkers and a second therapy score is based on
the patient's genetic biomarkers and expression biomarkers. First
and second therapy scores may be determined for different therapies
and/or different types of therapies. For example, first and second
therapy scores may be determined for an immune checkpoint blockade
therapy (e.g., anti-PD1 therapy) and a kinase inhibitor therapy
(e.g., Sunitinib), respectively. In another example, first and
second therapy scores may be determined for two different immune
checkpoint blockade therapies (e.g., anti-PD1 therapy and
anti-CTLA4 therapy).
[0205] Process 260 begins at act 262, where sequencing data for a
subject is obtained. Any type of sequencing data may be obtained,
for example, sequencing data from transcriptome, exome, and/or
genome sequencing of a patient's tumor biopsy. In some embodiments,
obtaining sequencing data comprises obtaining sequencing data from
a biological sample obtained from the subject and/or from a
database storing such information. Further aspects relating to
obtaining sequencing data are provided in section "Sample
Analysis".
[0206] Next, process 260 proceeds to act 264, where biomarker
information indicating distribution of values for biomarkers
associated with at least two therapies. In some embodiments,
information indicating a distribution of values is obtained for
each of one or more biomarkers associated with a first therapy, and
information indicating a distribution of values is obtained for
each of one or more biomarkers associated with a second therapy
different from the first therapy. Accessing biomarker information
may include obtaining biomarker information from a variety of
sources including, for example, one or more databases
[0207] Next, process 260 proceeds to act 266, where first and
second sets of normalized biomarker scores for the subject are
determined using sequencing data obtained at act 262 and biomarker
information obtained at act 264. First and second sets of
normalized biomarker scores for the subject are determined, in some
embodiments, using a reference subset of biomarkers comprising sets
of biomarker values for the same biomarkers in multiple reference
subjects. In that way, the subject's first and second sets of
biomarker scores are adjusted (e.g., normalized) to a common scale
based on a distribution of biomarker values in a reference subset
of biomarkers. Since the first set of biomarkers is associated with
one therapy and the second set of biomarkers is associated with
another therapy, the first and second sets of normalized biomarkers
may differ from each other, for example, in number of biomarkers
and/or types of biomarkers. Further aspects relating to determining
normalized biomarker scores are provided in section "From Biomarker
Values To Normalized Biomarker Scores".
[0208] Next, process 260 proceeds to act 268, where first and
second therapy scores for the first and second therapies are
determined based on normalized biomarker scores for each therapy. A
therapy score may be calculated using the normalized biomarker
scores as a sum, as a weighted sum, using a linear or generalized
linear model, using a statistical model, or combinations thereof.
The therapy score may be calculated using any suitable number of
normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized
biomarker scores. Further aspects relating to determining therapy
scores are provided in section "Predicting Therapy Response".
[0209] First and second therapy scores for first and second
therapies and/or biomarker information used for determining therapy
scores may be output to a user, in some embodiments, by displaying
the information to the user in a graphical user interface (GUI),
including the information in a report, sending an email to the
user, and/or in any other suitable way. For example, therapy scores
and other patient related information may be provided to a user in
a GUI as shown in FIGS. 9-14.
[0210] Systems and methods described herein may be used to select
patients for a clinical trial for a particular therapy based on the
patient's predicted response to that therapy determined using the
patient's biomarkers as described herein. The systems and methods
described herein may be used to identify a patient as a member of a
cohort for participation in a clinical trial.
[0211] FIG. 2E is a flowchart of an illustrative
computer-implemented process 280 for identifying a subject as a
member of a cohort using normalized biomarker scores, in accordance
with some embodiments of the technology described herein. A subject
may be identified as a member of a cohort for a clinical trial of
any type of therapy, for example, a chemotherapy, an immunotherapy,
an antibody therapy, and/or any combination thereof. The patient
may be identified as a member of a cohort that will be administered
the treatment or as a member of a cohort that will be administered
a placebo. In some embodiments, the patient may be not be
identified as a member of a cohort, and thus may be excluded from
participation in a clinical trial. Patients may be excluded from a
clinical trial, in some embodiments, if those patients have been
predicted to have an adverse reaction to a therapy determined using
the patient's biomarkers as described herein and/or the patient's
gene expression data as described in International patent
application number PCT/US18/37018, entitled "Systems and Methods
for Identifying Responders and Non-Responders to Immune Checkpoint
Blockade Therapy," filed Jun. 12, 2018, the entire contents of
which are incorporated herein by reference.
[0212] Process 280 begins at act 282, where sequencing data for a
subject is obtained. Any type of sequencing data may be obtained,
for example, sequencing data from transcriptome, exome, and/or
genome sequencing of a patient's tumor biopsy. In some embodiments,
obtaining sequencing data comprises obtaining sequencing data from
a biological sample obtained from the subject and/or from a
database storing such information. Further aspects relating to
obtaining sequencing data are provided in section "Sample
Analysis".
[0213] Next, process 280 proceeds to act 284, where biomarker
information indicating a distribution of values for each of one or
more biomarkers associated with a therapy is accessed. Accessing
biomarker information may include obtaining biomarker information
from a variety of sources, for example, one or more databases.
[0214] Next, process 280 proceeds to act 286, where normalized
biomarker scores for the subject are determined using sequencing
data and biomarker information. Normalized biomarker scores for the
subject are determined, in some embodiments, using a reference
subset of biomarkers comprising sets of biomarker values for the
same biomarkers in multiple reference subjects. In that way, the
subject's biomarker score is adjusted (e.g., normalized) to a
common scale based on a distribution of biomarker values in a
reference subset of biomarkers. Further aspects relating to
determining normalized biomarker scores are provided in section
"From Biomarker Values To Normalized Biomarker Scores".
[0215] Next, process 280 proceeds to act 288, where a subject is
identified as a member of a cohort for participating in a clinical
trial using biomarker scores. An identified subject, in some
embodiments, may be a subject that is likely to respond positively
to the therapy being administered in the clinical trial. Such
information may be output to a user, in some embodiments, by
displaying the information to the user in a graphical user
interface (GUI), including the information in a report, sending an
email to the user, and/or in any other suitable way.
[0216] In this way, a patient can be identified and selected for
participation in a clinical trial based on the patient's biomarker
scores. Patients can also be identified for exclusion from the
clinical trial, for example, patients predicted not likely to
respond positively to the therapy and/or patients predicted to have
an adverse reaction to the therapy.
Presentation of Predicted Therapy Response or Impact Score
[0217] In some embodiments, a software program may provide a user
with a visual representation presenting information related to a
patient's biomarker values (e.g., a biomarker score, and/or a
therapy score, and/or an impact score), and predicted efficacy or
determined efficacy of one or more therapies using a graphical user
interface (GUI).
[0218] In response to being launched, the interactive GUI may
provide the user of the software program with a visual
representation of a patient's biomarker values and/or additional
information related to the biomarker. FIGS. 6A-6C are screenshots
presenting such information to a user of the software program.
[0219] FIG. 6A is a screenshot presenting a patient's biomarker
information associated with different immunotherapies that may be
used to treat the patient. Shading reflects normalized biomarker
value in terms of gradient from -1 to 1. Shading intensity
increasing as the biomarker value is increased. Shading with lines
is assigned to positive biomarker values to distinguish them from
negative biomarker values. Numeric "weight" of a biomarker is
reflected in the width of the block with larger block width
indicating a higher numeric weight.
[0220] As shown in FIG. 6A, a greater number of biomarkers with
positive scores were calculated for anti-PD1 therapy indicating a
predicted positive therapeutic effect of anti-PD1 therapy for a
patient. By contrast, a greater number of biomarkers with negative
scores were calculated for anti-VEGF therapy indicating a predicted
negative therapeutic effect of anti-VEGF therapy for a patient.
Numbers of positive biomarkers and negative biomarkers for a
particular therapy may be similar for a patient. In such a case,
the therapeutic effects of that therapy for the patient may not be
predicted (i.e., may not be accurately predicted). Medium biomarker
values for a particular therapy may also indicate that the
therapeutic effects of that therapy for the patient may not be
predicted (i.e., may not be accurately predicted).
[0221] FIG. 6B is a visual representation illustrating therapy
scores calculated using normalized biomarker values shown in FIG.
6A. Negative therapy scores are shown on the left side of the
y-axis, and positive therapy scores are shown on the right side of
the y-axis. Positive therapy scores are also differentiated from
negative therapy scores by shading with lines.
[0222] A user may interact with the GUI to obtain additional
information about a biomarker. FIG. 6C is a screenshot presenting
information related to each biomarker and patient specific
information related to that biomarker. Information presented
includes, from left to right, a block representing each biomarker,
a description of the biomarker, a graph showing the distribution of
biomarker values, and a general description of the biomarker value
as "high," "low," or "neutral". The arrow in the graph indicates
the patient's biomarker value. In some embodiments a normalized
biomarker score may be labeled as a high score when the normalized
biomarker score is in the top threshold percent (e.g., 1%, 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) of a distribution of
values. In some embodiments, a normalized biomarker score may be
labeled as a low score when the normalized biomarker score is in
the bottom threshold percent (e.g., 1%, 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%) of a distribution of values. In certain
embodiments, a normalized biomarker score may be considered neutral
if it is not in the top threshold or the bottom threshold of a
distribution of values.
[0223] FIG. 9 is a graphic illustrating different types of screens
that may be shown to a user of the software program. Each of the
different screens illustrated in FIG. 9 may be used to present
different types of information to the user. A screenshot of a
control screen of the software program is shown in the middle of
FIG. 9. The control screen includes portions for presenting
information relating to treatment selection, tumor properties, and
clinical evidence of treatment efficacy and is described further
with respect to FIGS. 10-15.
[0224] A user may interact with the control screen to obtain
additional information about, for example, immunotherapy selection,
targeted therapy selection, combination therapy design, tumor
properties and tumor microenvironment, clinical evidence of
targeted therapy efficacy, and clinical evidence of immunotherapy
efficacy. The user may select a portion of the control screen
(e.g., the immunotherapy portion) to view one or more additional
screens presenting information relating to the selected portion. As
shown in FIG. 9, arrows point from a portion of the control screen
that may be selected toward the screens presenting additional
information related to the selected portion.
[0225] For example, the user may select the immunotherapy selection
portion of the control screen to view one or more screens
presenting information relating to various immunotherapies,
biomarkers associated with an immunotherapy (e.g., genetic
biomarkers, cellular biomarkers, and expression biomarkers), immune
cell properties of the patient's tumor, and clinical trials (e.g.,
information from and/or regarding published clinical trials and
ongoing clinical trials).
[0226] In another example, the user may select the targeted therapy
selection portion of the control screen to view one or more screens
presenting information relating to various targeted therapies,
biomarkers associated with targeted therapies (e.g., genetic
biomarkers, cellular biomarkers, and/or expression biomarkers),
properties of the patient's tumor associated with the targeted
therapy, and clinical trials (e.g., published clinical trials and
ongoing clinical trials).
[0227] In another example, the user may select the
molecular-functional portrait (MF profile) portion of the control
screen to view one or more screens presenting information relating
to the patient's tumor microenvironment. Such information may
include information about tumor properties (e.g., proliferation
rate), angiogenesis, metastasis, cellular composition, cancer
associated fibroblasts, pro-tumor immune environment, and
anti-tumor immune environment.
[0228] In yet another example, the user may select the clinical
evidence of treatment efficacy portion of the control screen to
view one or more screens presenting information relating to a
therapy (e.g., an immunotherapy or targeted therapy). Such
information may include description of the therapy, therapy
efficacy, potential adverse effects, related publications,
treatment regimen, and patient survival data.
[0229] In a further example, the user may select a portion of the
control screen to view one or more screens associated with an
impact score for one or more candidate therapies, wherein the
impact score is indicative of response of the subject to
administration of the one or more candidate therapies.
[0230] A user of the software program may interact with the GUI to
log into the software program. The user may select a stored report
to view a screen presenting information relating to the selected
report. The user may select the create new report portion to view a
screen for creating a new report.
[0231] FIG. 10 is a screenshot presenting the selected patient's
report including information related to the patient's sequencing
data, the patient, and the patient's cancer. The therapy biomarkers
portion (as shown in the left panel) presents information related
to available therapies (e.g., immunotherapies and targeted
therapies) and their predicted efficacy in the selected patient.
Additional predictions of the efficacy of a therapy in the patient
are provided in the machine predictor portion and additional
portion (as shown in the left panel). The MF profile portion
presents information relating to the molecular characteristics of a
tumor including tumor genetics, pro-tumor microenvironment factors,
and anti-tumor immune response factors (as shown in the middle
panel). The clinical trials portion provides information relating
to clinical trials (as shown in the right panel). The monotherapy
or combinational therapy portion (as shown in the middle panel) may
be selected by the user to interactively design a personalized
treatment for a patient.
[0232] A user may select various portions of the screen to view
additional information. For example, a user may select anti-PD1 in
the immunotherapy biomarkers portion of the screen (as shown in the
left panel) to view information relating to anti-PD1 treatment
including biomarkers associated with anti-PD1 and tumor cell
processes associated with anti-PD1 treatment.
[0233] FIG. 11 is a screenshot presenting information related to
anti-PD1 immunotherapy provided in response to selecting anti-PD1
immunotherapy (as shown by highlighting) in the immunotherapy
biomarkers portion of the screen (as shown in the left panel).
Information relating to biomarkers associated with anti-PD1
immunotherapy is provided in the biomarkers portion (as shown in
the right panel). The biomarkers portion presents genetic
biomarkers, cellular biomarkers, and expression biomarkers, as well
as patient specific information related to those biomarkers.
[0234] The user may select any one of the biomarkers presented in
the biomarkers markers portion to view additional information
relating to that biomarker including general information about the
selected biomarker, patient specific information relating to the
selected biomarker, information relating to tumor molecular
processes associated with the selected biomarker, and treatment
related information associated with the selected biomarker.
[0235] In response to selection by a user, the selected biomarker
may be visually highlighted. As a set of non-limiting examples, a
"visually highlighted" element may be highlighted through a
difference in font (e.g., by italicizing, bolding, and/or
underlining), by surrounding the section with a visual object
(e.g., a box), by "popping" the element out (e.g., by increasing
the zoom for that element), by changing the color of an element, by
shading the element, by incorporation of movement into the element
(e.g., by causing the element to move), any combination of the
foregoing in a portion or the whole of the element, or in any other
suitable way. FIG. 12 is a screenshot presenting the mutational
burden biomarker (as shown by highlighting) was selected by the
user. The user may select another portion of the mutational burden
biomarker to view a screen presenting information relating to the
mutational burden biomarker such as relevant publications.
[0236] FIG. 13 is a screenshot presenting information relating to
the mutational burden biomarker (as shown in the middle panel)
provided in response to the user selecting the mutational burden
biomarker. The information may include a description of the
biomarker, how the biomarker was calculated, the patient's
particular biomarker value compared to other patients (as shown in
a histogram), and information from publications relating to the
selected biomarker.
[0237] The system allows a user to interactively view biomarker
information as it relates to a predicted response to a therapy.
Clinical evidence of treatment efficacy for a therapy (e.g., an
immunotherapy or a targeted therapy) may be interactively viewed by
the user.
[0238] FIG. 14 is a screenshot presenting clinical trial data
relating to anti-PD1 therapy effectivity in patients having stage
IV metastatic melanoma (as shown in the right panel) provided in
response to the user selecting anti-PD1 immunotherapy (as shown in
the left panel).
Therapeutics and Methods of Therapy
[0239] In certain methods or systems described herein, no
recommendation is made regarding administration of a therapy to a
subject (e.g., a human). In certain methods described herein, an
effective amount of anti-cancer therapy described herein may be
administered or recommended for administration to a subject (e.g.,
a human) in need of the treatment via a suitable route (e.g.,
intravenous administration).
[0240] The subject to be treated by the methods described herein
may be a human patient having, suspected of having, or at risk for
a cancer. Examples of a cancer include, but are not limited to,
melanoma, lung cancer, brain cancer, breast cancer, colorectal
cancer, pancreatic cancer, liver cancer, prostate cancer, skin
cancer, kidney cancer, bladder cancer, or prostate cancer. The
subject to be treated by the methods described herein may be a
mammal (e.g., may be a human). Mammals may include, but are not
limited to: farm animals (e.g., livestock), sport animals,
laboratory animals, pets, primates, horses, dogs, cats, mice, and
rats.
[0241] A subject having a cancer may be identified by routine
medical examination, e.g., laboratory tests, biopsy, PET scans, CT
scans, or ultrasounds. A subject suspected of having a cancer might
show one or more symptoms of the disorder, e.g., unexplained weight
loss, fever, fatigue, cough, pain, skin changes, unusual bleeding
or discharge, and/or thickening or lumps in parts of the body. A
subject at risk for a cancer may be a subject having one or more of
the risk factors for that disorder. For example, risk factors
associated with cancer include, but are not limited to, (a) viral
infection (e.g., herpes virus infection), (b) age, (c) family
history, (d) heavy alcohol consumption, (e) obesity, and (f)
tobacco use.
[0242] Any anti-cancer therapy or anti-cancer therapeutic agent may
be used in conjunction with the methods and systems described
herein. In some embodiments, an anti-cancer therapeutic agent is an
antibody, an immunotherapy, a molecular targeted therapy, a
radiation therapy, a surgical therapy, and/or a chemotherapy.
[0243] Examples of the antibody anti-cancer agents include, but are
not limited to, alemtuzumab (Campath), trastuzumab (Herceptin),
Ibritumomab tiuxetan (Zevalin), Brentuximab vedotin (Adcetris),
Ado-trastuzumab emtansine (Kadcyla), blinatumomab (Blincyto),
Bevacizumab (Avastin), Cetuximab (Erbitux), ipilimumab (Yervoy),
nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab
(Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), and
panitumumab (Vectibix).
[0244] Examples of an immunotherapy include, but are not limited
to, a PD-1 inhibitor or a PD-L1 inhibitor, a CTLA-4 inhibitor,
adoptive cell transfer, therapeutic cancer vaccines, oncolytic
virus therapy, T-cell therapy, and immune checkpoint
inhibitors.
[0245] Examples of a molecular targeted therapy include, but are
not limited to: Uprosertib, Alectinib, Crizotinib, Alisertib,
Barasertib, Gilteritinib, Navitoclax, Bosutinib, Dasatinib,
Nilotinib, Ponatinib, Imatinib, Dabrafenib, Vemurafenib,
Encorafenib, Acalabrutinib, Ibrutinib, Verapamil, Tacrolimus,
Abemaciclib, Ribociclib, Palbociclib, Celecoxib, Apricoxib,
Selinexor, Plerixafor, Pinometostat, Rociletinib, Pyrotinib,
Erlotinib, Gefitinib, Afatinib, Osimertinib, Varlitinib, Icotinib,
Lapatinib, Neratinib, Tazemetostat, Tipifarnib, Dovitinib,
Lucitanib, Erdafitinib, Crenolanib, Atorvastatin, Onalespib,
Enasidenib, Sitagliptin, Ruxolitinib, Tofacitinib, Idasanutlin,
Selumetinib, Trametinib, Cobimetinib, Binimetinib, Foretinib,
Capmatinib, Tivantinib, Volitinib, Vistusertib, Everolimus,
Sirolimus, Torkinib, Temsirolimus, Ridaforolimus, Metformin,
Apitolisib, Dactolisib, Brontictuzumab, Omaveloxolone, Dacomitinib,
Sapitinib, Poziotinib, Cabozantinib, Regorafenib, Lestaurtinib,
Midostaurin, Nintedanib, Pexidartinib, Quizartinib, Sorafenib,
Sunitinib, Vandetanib, Entrectinib, Pazopanib, Masitinib,
Anlotinib, Brigatinib, Olaparib, Apatinib, Niraparib, Rucaparib,
Veliparib, Roflumilast, Idelalisib, Copanlisib, Buparlisib,
Taselisib, Pictilisib, Umbralisib, Duvelisib, Alpelisib,
Volasertib, Vismodegib, Sonidegib, Saracatinib, Entospletinib,
Fostamatinib, Cerdulatinib, Larotrectinib, Auranofin, Axitinib,
Cediranib, Lenvatinib, and Alvocidib.
[0246] Examples of radiation therapy include, but are not limited
to, ionizing radiation, gamma-radiation, neutron beam radiotherapy,
electron beam radiotherapy, proton therapy, brachytherapy, systemic
radioactive isotopes, and radiosensitizers.
[0247] Examples of a surgical therapy include, but are not limited
to, a curative surgery (e.g., tumor removal surgery), a preventive
surgery, a laparoscopic surgery, and a laser surgery.
[0248] Examples of the chemotherapeutic agents include, but are not
limited to, Carboplatin or Cisplatin, Docetaxel, Gemcitabine,
Nab-Paclitaxel, Paclitaxel, Pemetrexed, and Vinorelbine.
[0249] Additional examples of chemotherapy include, but are not
limited to, Platinating agents, such as Carboplatin, Oxaliplatin,
Cisplatin, Nedaplatin, Satraplatin, Lobaplatin, Triplatin,
Tetranitrate, Picoplatin, Prolindac, Aroplatin and other
derivatives; Topoisomerase I inhibitors, such as Camptothecin,
Topotecan, irinotecan/SN38, rubitecan, Belotecan, and other
derivatives; Topoisomerase II inhibitors, such as Etoposide
(VP-16), Daunorubicin, a doxorubicin agent (e.g., doxorubicin,
doxorubicin hydrochloride, doxorubicin analogs, or doxorubicin and
salts or analogs thereof in liposomes), Mitoxantrone, Aclarubicin,
Epirubicin, Idarubicin, Amrubicin, Amsacrine, Pirarubicin,
Valrubicin, Zorubicin, Teniposide and other derivatives;
Antimetabolites, such as Folic family (Methotrexate, Pemetrexed,
Raltitrexed, Aminopterin, and relatives or derivatives thereof);
Purine antagonists (Thioguanine, Fludarabine, Cladribine,
6-Mercaptopurine, Pentostatin, clofarabine, and relatives or
derivatives thereof) and Pyrimidine antagonists (Cytarabine,
Floxuridine, Azacitidine, Tegafur, Carmofur, Capacitabine,
Gemcitabine, hydroxyurea, 5-Fluorouracil (5FU), and relatives or
derivatives thereof); Alkylating agents, such as Nitrogen mustards
(e.g., Cyclophosphamide, Melphalan, Chlorambucil, mechlorethamine,
Ifosfamide, mechlorethamine, Trofosfamide, Prednimustine,
Bendamustine, Uramustine, Estramustine, and relatives or
derivatives thereof); nitrosoureas (e.g., Carmustine, Lomustine,
Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin, and
relatives or derivatives thereof); Triazenes (e.g., Dacarbazine,
Altretamine, Temozolomide, and relatives or derivatives thereof);
Alkyl sulphonates (e.g., Busulfan, Mannosulfan, Treosulfan, and
relatives or derivatives thereof); Procarbazine; Mitobronitol, and
Aziridines (e.g., Carboquone, Triaziquone, ThioTEPA,
triethylenemalamine, and relatives or derivatives thereof);
Antibiotics, such as Hydroxyurea, Anthracyclines (e.g., doxorubicin
agent, daunorubicin, epirubicin and relatives or derivatives
thereof); Anthracenediones (e.g., Mitoxantrone and relatives or
derivatives thereof); Streptomyces family antibiotics (e.g.,
Bleomycin, Mitomycin C, Actinomycin, and Plicamycin); and
ultraviolet light.
[0250] "An effective amount" as used herein refers to the amount of
each active agent required to confer therapeutic effect on the
subject, either alone or in combination with one or more other
active agents. Effective amounts vary, as recognized by those
skilled in the art, depending on the particular condition being
treated, the severity of the condition, the individual patient
parameters including age, physical condition, size, gender and
weight, the duration of the treatment, the nature of concurrent
therapy (if any), the specific route of administration and like
factors within the knowledge and expertise of the health
practitioner. These factors are well known to those of ordinary
skill in the art and can be addressed with no more than routine
experimentation. It is generally preferred that a maximum dose of
the individual components or combinations thereof be used, that is,
the highest safe dose according to sound medical judgment. It will
be understood by those of ordinary skill in the art, however, that
a patient or clinician may insist upon a lower dose or tolerable
dose for medical reasons, psychological reasons, or for virtually
any other reason(s).
[0251] Empirical considerations, such as the half-life of a
therapeutic compound, generally contribute to the determination of
the dosage. For example, antibodies that are compatible with the
human immune system, such as humanized antibodies or fully human
antibodies, may be used to prolong half-life of the antibody and to
prevent the antibody being attacked by the host's immune system.
Frequency of administration may be determined and adjusted over the
course of therapy, and is generally (but not necessarily) based on
treatment, and/or suppression, and/or amelioration, and/or delay of
a cancer. Alternatively, sustained continuous release formulations
of an anti-cancer therapeutic agent may be appropriate. Various
formulations and devices for achieving sustained release are known
in the art.
[0252] In some embodiments, dosages for an anti-cancer therapeutic
agent as described herein may be determined empirically in
individuals who have been administered one or more doses of the
anti-cancer therapeutic agent. Individuals may be administered
incremental dosages of the anti-cancer therapeutic agent. To assess
efficacy of an administered anti-cancer therapeutic agent, one or
more aspects of a cancer (e.g., tumor formation or tumor growth)
may be analyzed.
[0253] Generally, for administration of any of the anti-cancer
antibodies described herein, an initial candidate dosage may be
about 2 mg/kg. For the purpose of the present disclosure, a typical
daily dosage might range from about any of 0.1 .mu.g/kg to 3
.mu.g/kg to 30 .mu.g/kg to 300 .mu.g/kg to 3 mg/kg, to 30 mg/kg to
100 mg/kg or more, depending on the factors mentioned above. For
repeated administrations over several days or longer, depending on
the condition, the treatment is sustained until a desired
suppression or amelioration of symptoms occurs or until sufficient
therapeutic levels are achieved to alleviate a cancer, or one or
more symptoms thereof. An exemplary dosing regimen comprises
administering an initial dose of about 2 mg/kg, followed by a
weekly maintenance dose of about 1 mg/kg of the antibody, or
followed by a maintenance dose of about 1 mg/kg every other week.
However, other dosage regimens may be useful, depending on the
pattern of pharmacokinetic decay that the practitioner (e.g., a
medical doctor) wishes to achieve. For example, dosing from
one-four times a week is contemplated. In some embodiments, dosing
ranging from about 3 .mu.g/mg to about 2 mg/kg (such as about 3
.mu.g/mg, about 10 .mu.g/mg, about 30 .mu.g/mg, about 100 .mu.g/mg,
about 300 .mu.g/mg, about 1 mg/kg, and about 2 mg/kg) may be used.
In some embodiments, dosing frequency is once every week, every 2
weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks,
every 8 weeks, every 9 weeks, or every 10 weeks; or once every
month, every 2 months, or every 3 months, or longer. The progress
of this therapy may be monitored by conventional techniques and
assays and/or by monitoring the progress of the disease or cancer
as described herein. The dosing regimen (including the therapeutic
used) may vary over time.
[0254] When the anti-cancer therapeutic agent is not an antibody,
it may be administered at the rate of about 0.1 to 300 mg/kg of the
weight of the patient divided into one to three doses, or as
disclosed herein. In some embodiments, for an adult patient of
normal weight, doses ranging from about 0.3 to 5.00 mg/kg may be
administered. The particular dosage regimen, e.g., dose, timing,
and/or repetition, will depend on the particular subject and that
individual's medical history, as well as the properties of the
individual agents (such as the half-life of the agent, and other
considerations well known in the art).
[0255] For the purpose of the present disclosure, the appropriate
dosage of an anti-cancer therapeutic agent will depend on the
specific anti-cancer therapeutic agent(s) (or compositions thereof)
employed, the type and severity of cancer, whether the anti-cancer
therapeutic agent is administered for preventive or therapeutic
purposes, previous therapy, the patient's clinical history and
response to the anti-cancer therapeutic agent, and the discretion
of the attending physician. Typically the clinician will administer
an anti-cancer therapeutic agent, such as an antibody, until a
dosage is reached that achieves the desired result.
[0256] Administration of an anti-cancer therapeutic agent can be
continuous or intermittent, depending, for example, upon the
recipient's physiological condition, whether the purpose of the
administration is therapeutic or prophylactic, and other factors
known to skilled practitioners. The administration of an
anti-cancer therapeutic agent (e.g., an anti-cancer antibody) may
be essentially continuous over a preselected period of time or may
be in a series of spaced dose, e.g., either before, during, or
after developing cancer.
[0257] As used herein, the term "treating" refers to the
application or administration of a composition including one or
more active agents to a subject, who has a cancer, a symptom of a
cancer, or a predisposition toward a cancer, with the purpose to
cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve,
or affect the cancer or one or more symptoms of the cancer, or the
predisposition toward a cancer. In some embodiments, the methods
and systems herein may comprise recommendation of a treatment
rather than treatment itself. In some embodiments, no
recommendation of a treatment will be made. In certain embodiments,
one or more potential treatments may be "ranked" or compared
according to their predicted efficacy and/or subject or patient
outcome. In certain embodiments, one or more potential treatments
will not be "ranked" or compared according to their predicted
efficacy and/or subject or patient outcome. In some embodiments,
information about a therapy (e.g., the therapy score) for a patient
will be outputted. In specific embodiments, such information may be
outputted to a user (e.g., a doctor or clinician).
[0258] Alleviating a cancer includes delaying the development or
progression of the disease, or reducing disease severity (e.g., by
at least one parameter). Alleviating the disease does not
necessarily require curative results. As used therein, "delaying"
the development of a disease (e.g., a cancer) means to defer,
hinder, slow, retard, stabilize, and/or postpone progression of the
disease. This delay can be of varying lengths of time, depending on
the history of the disease and/or individuals being treated. A
method that "delays" or alleviates the development or progress of a
disease, or delays the onset of one or more complications of the
disease, is a method that reduces probability of developing one or
more symptoms of the disease in a given time frame and/or reduces
extent of the symptoms in a given time frame, when compared to not
using the method. Such comparisons are typically based on clinical
studies, using a number of subjects sufficient to give a
statistically significant result.
[0259] "Development" or "progression" of a disease means initial
manifestations and/or ensuing progression of the disease.
Development of the disease can be detected and assessed using
clinical techniques known in the art. Alternatively or in addition
to the clinical techniques known in the art, development of the
disease may be detectable and assessed based on biomarkers
described herein. However, development also refers to progression
that may be undetectable. For purpose of this disclosure,
development or progression refers to the biological course of the
symptoms. "Development" includes occurrence, recurrence, and onset.
As used herein "onset" or "occurrence" of a cancer includes initial
onset and/or recurrence.
[0260] In some embodiments, the anti-cancer therapeutic agent
(e.g., an antibody) described herein is administered to a subject
in need of the treatment at an amount sufficient to reduce cancer
(e.g., tumor) growth by at least 10% (e.g., 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90% or greater). In some embodiments, the
anti-cancer therapeutic agent (e.g., an antibody) described herein
is administered to a subject in need of the treatment at an amount
sufficient to reduce cancer cell number or tumor size by at least
10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more). In
other embodiments, the anti-cancer therapeutic agent is
administered in an amount effective in altering cancer type (e.g.,
from a more severe to a less severe type; or from a worse prognosis
to a better prognosis). Alternatively, the anti-cancer therapeutic
agent is administered in an amount effective in reducing tumor
formation, size, or metastasis.
[0261] Conventional methods, known to those of ordinary skill in
the art of medicine, may be used to administer the anti-cancer
therapeutic agent to the subject, depending upon the type of
disease to be treated or the site of the disease. The anti-cancer
therapeutic agent can also be administered via other conventional
routes, e.g., administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally, or via an
implanted reservoir. The term "parenteral" as used herein includes
subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional, and intracranial injection or infusion
techniques. In addition, an anti-cancer therapeutic agent may be
administered to the subject via injectable depot routes of
administration such as using 1-, 3-, or 6-month depot injectable or
biodegradable materials and methods.
[0262] Injectable compositions may contain various carriers such as
vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate,
ethyl carbonate, isopropyl myristate, ethanol, and polyols (e.g.,
glycerol, propylene glycol, liquid polyethylene glycol, and the
like). For intravenous injection, water soluble anti-cancer
therapeutic agents can be administered by the drip method, whereby
a pharmaceutical formulation containing the antibody and a
physiologically acceptable excipients is infused. Physiologically
acceptable excipients may include, for example, 5% dextrose, 0.9%
saline, Ringer's solution, and/or other suitable excipients.
Intramuscular preparations, e.g., a sterile formulation of a
suitable soluble salt form of the anti-cancer therapeutic agent,
can be dissolved and administered in a pharmaceutical excipient
such as Water-for-Injection, 0.9% saline, and/or 5% glucose
solution.
[0263] In one embodiment, an anti-cancer therapeutic agent is
administered via site-specific or targeted local delivery
techniques. Examples of site-specific or targeted local delivery
techniques include various implantable depot sources of the agent
or local delivery catheters, such as infusion catheters, an
indwelling catheter, or a needle catheter, synthetic grafts,
adventitial wraps, shunts and stents or other implantable devices,
site specific carriers, direct injection, or direct application.
See, e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No.
5,981,568, the contents of each of which are incorporated by
reference herein for this purpose.
[0264] Targeted delivery of therapeutic compositions containing an
antisense polynucleotide, expression vector, or subgenomic
polynucleotides can also be used. Receptor-mediated DNA delivery
techniques are described in, for example, Findeis et al., Trends
Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods
And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994);
Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem.
(1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. USA (1990)
87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. The contents of
each of the foregoing are incorporated by reference herein for this
purpose.
[0265] Therapeutic compositions containing a polynucleotide may be
administered in a range of about 100 ng to about 200 mg of DNA for
local administration in a gene therapy protocol. In some
embodiments, concentration ranges of about 500 ng to about 50 mg,
about 1 .mu.g to about 2 mg, about 5 .mu.g to about 500 .mu.g, and
about 20 .mu.g to about 100 .mu.g of DNA or more can also be used
during a gene therapy protocol.
[0266] Therapeutic polynucleotides and polypeptides can be
delivered using gene delivery vehicles. The gene delivery vehicle
can be of viral or non-viral origin (e.g., Jolly, Cancer Gene
Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845;
Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature
Genetics (1994) 6:148). The contents of each of the foregoing are
incorporated by reference herein for this purpose. Expression of
such coding sequences can be induced using endogenous mammalian or
heterologous promoters and/or enhancers. Expression of the coding
sequence can be either constitutive or regulated.
[0267] Viral-based vectors for delivery of a desired polynucleotide
and expression in a desired cell are well known in the art.
Exemplary viral-based vehicles include, but are not limited to,
recombinant retroviruses (see, e.g., PCT Publication Nos. WO
90/07936; WO 94/03622; WO 93/25698; WO 93/25234; WO 93/11230; WO
93/10218; WO 91/02805; U.S. Pat. Nos. 5,219,740 and 4,777,127; GB
Patent No. 2,200,651; and EP Patent No. 0 345 242),
alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki
forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC
VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus
(ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)), and
adeno-associated virus (AAV) vectors (see, e.g., PCT Publication
Nos. WO 94/12649, WO 93/03769; WO 93/19191; WO 94/28938; WO
95/11984 and WO 95/00655). Administration of DNA linked to killed
adenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can
also be employed. The contents of each of the foregoing are
incorporated by reference herein for this purpose.
[0268] Non-viral delivery vehicles and methods can also be
employed, including, but not limited to, polycationic condensed DNA
linked or unlinked to killed adenovirus alone (see, e.g., Curiel,
Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J.
Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles
cells (see, e.g., U.S. Pat. No. 5,814,482; PCT Publication Nos. WO
95/07994; WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic
charge neutralization or fusion with cell membranes. Naked DNA can
also be employed. Exemplary naked DNA introduction methods are
described in PCT Publication No. WO 90/11092 and U.S. Pat. No.
5,580,859. Liposomes that can act as gene delivery vehicles are
described in U.S. Pat. No. 5,422,120; PCT Publication Nos. WO
95/13796; WO 94/23697; WO 91/14445; and EP Patent No. 0524968.
Additional approaches are described in Philip, Mol. Cell. Biol.
(1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994)
91:1581. The contents of each of the foregoing are incorporated by
reference herein for this purpose.
[0269] It is also apparent that an expression vector can be used to
direct expression of any of the protein-based anti-cancer
therapeutic agents (e.g., an anti-cancer antibody). For example,
peptide inhibitors that are capable of blocking (from partial to
complete blocking) a cancer causing biological activity are known
in the art.
[0270] In some embodiments, more than one anti-cancer therapeutic
agent, such as an antibody and a small molecule inhibitory
compound, may be administered to a subject in need of the
treatment. The agents may be of the same type or different types
from each other. At least one, at least two, at least three, at
least four, or at least five different agents may be
co-administered. Generally anti-cancer agents for administration
have complementary activities that do not adversely affect each
other. Anti-cancer therapeutic agents may also be used in
conjunction with other agents that serve to enhance and/or
complement the effectiveness of the agents.
[0271] Treatment efficacy can be predicted as described herein for
a patient prior to a treatment. Alternatively or in addition to,
treatment efficacy can be predicted and/or determined as described
herein over the course of treatment (e.g., before, during, and
after treatment). See, e.g., Example 4 and Example 5 below.
Combination Therapy
[0272] Compared to monotherapies, combinations of treatment
approaches showed higher efficacy in many studies, but the choice
of remedies to be combined and designing the combination therapy
regimen remain speculative. Given that the number of possible
combinations is now extremely high, there is great need for a tool
that would help to select drugs and combinations of remedies based
on objective information about a particular patient. Use of
biomarkers as described herein for designing or electing a specific
combination therapy establishes a scientific basis for choosing the
optimal combination of preparations.
[0273] As noted above, also provided herein are methods of treating
a cancer or recommending treating a cancer using any combination of
anti-cancer therapeutic agents or one or more anti-cancer
therapeutic agents and one or more additional therapies (e.g.,
surgery and/or radiotherapy). The term combination therapy, as used
herein, embraces administration of more than one treatment (e.g.,
an antibody and a small molecule or an antibody and radiotherapy)
in a sequential manner, that is, wherein each therapeutic agent is
administered at a different time, as well as administration of
these therapeutic agents, or at least two of the agents or
therapies, in a substantially simultaneous manner.
[0274] Sequential or substantially simultaneous administration of
each agent or therapy can be affected by any appropriate route
including, but not limited to, oral routes, intravenous routes,
intramuscular, subcutaneous routes, and direct absorption through
mucous membrane tissues. The agents or therapies can be
administered by the same route or by different routes. For example,
a first agent (e.g., a small molecule) can be administered orally,
and a second agent (e.g., an antibody) can be administered
intravenously.
[0275] As used herein, the term "sequential" means, unless
otherwise specified, characterized by a regular sequence or order,
e.g., if a dosage regimen includes the administration of an
antibody and a small molecule, a sequential dosage regimen could
include administration of the antibody before, simultaneously,
substantially simultaneously, or after administration of the small
molecule, but both agents will be administered in a regular
sequence or order. The term "separate" means, unless otherwise
specified, to keep apart one from the other. The term
"simultaneously" means, unless otherwise specified, happening or
done at the same time, i.e., the agents of the disclosure are
administered at the same time. The term "substantially
simultaneously" means that the agents are administered within
minutes of each other (e.g., within 10 minutes of each other) and
intends to embrace joint administration as well as consecutive
administration, but if the administration is consecutive it is
separated in time for only a short period (e.g., the time it would
take a medical practitioner to administer two agents separately).
As used herein, concurrent administration and substantially
simultaneous administration are used interchangeably. Sequential
administration refers to temporally separated administration of the
agents or therapies described herein.
[0276] Combination therapy can also embrace the administration of
the anti-cancer therapeutic agent (e.g., an antibody) in further
combination with other biologically active ingredients (e.g., a
vitamin) and non-drug therapies (e.g., surgery or
radiotherapy).
[0277] It should be appreciated that any combination of anti-cancer
therapeutic agents may be used in any sequence for treating a
cancer. The combinations described herein may be selected on the
basis of a number of factors, which include but are not limited to
the effectiveness of altering a biomarker, reducing tumor formation
or tumor growth, and/or alleviating at least one symptom associated
with the cancer, or the effectiveness for mitigating the side
effects of another agent of the combination. For example, a
combined therapy as provided herein may reduce any of the side
effects associated with each individual members of the combination,
for example, a side effect associated with an administered
anti-cancer agent.
EXAMPLES
[0278] In order that the systems and methods described herein may
be more fully understood, the following examples are set forth. The
examples described in this application are offered to illustrate
the methods and systems provided herein and are not to be construed
in any way as limiting their scope.
Example 1: Calculating Normalized Biomarker Values
Obtaining Biomarker Sets
[0279] Any number of biomarkers may be used to predict therapy
efficacy using a technique provided herein. Biomarkers used herein
were obtained from published clinical studies shown in Table 1.
TABLE-US-00001 TABLE 1 Datasets used for calculating therapy
scores. Number of Therapy Dataset Diagnosis biomarkers aPD1 therapy
Hugo et al. Melanoma 46 aCTLA4 therapy Van Allen et al. Melanoma 17
IFNa therapy TCGA SKCM Melanoma 43 MAGEA-3 vaccine MAGEA3 dataset
Melanoma 13 GSE35640 Bevacizumab BEV-bladder-GSE60331 Melanoma 11
Rituximab Based MALY-DE ICGC Follicular 18 lymphoma
[0280] In the instant example, biomarkers that split the patient
cohorts treated with a particular therapy by a clinical measure
(e.g., overall survival (OS), progression-free survival (PFS),
objective response rate (ORR), ect.) were used. For example, in
patients treated with an anti-PD1 therapy, the PFS for patients
having a high number of mutations was 14.5 months and the PFS for
patients having a low number of mutations was 3.6 months. Thus, the
number of mutations was used as a parameter for predicting therapy
efficacy.
[0281] Biomarkers were defined as either positive biomarkers or
negative biomarkers based on whether the parameter value of the
biomarker corresponds to an increase or decrease in therapy
response. Biomarkers were defined as positive biomarkers if their
biomarker parameter value correlating to a positive therapy outcome
was high. Biomarkers were defined as negative biomarkers if their
biomarker parameter value correlating to a negative therapy outcome
was high.
[0282] A detailed set of biomarkers for each therapy is presented
in Table 2.
TABLE-US-00002 TABLE 2 Biomarkers obtained from published datasets.
Therapy Biomarkers aPD1 Affinity of AXL B2M LOF mutation BRAF
mutation therapy neontigens BRCA2 mutation Cancer gene panels
Cancer gene panels CCL13 (CGPs) FM-CGP (CGPs) HSL-CGP CCL2 CCL7
CCL8 CD8+ cell density in the tumor invasive margin CD8+ cell
number CDH1 CVEGFC CX3CL1 expression CXCR2 expression Dendritic
cell number EGFR expression Endothelial cells Eosinophil number
ESRP1 expression Fibroblasts Granzyme B expression JAK1 LOF
mutation JAK2 LOF mutation LDH level Lymphocyte number M1
macrophage M1/M2 macrophage MDSC % MHC-II expression number ratio
MHC-II expression Missmatch-repair MITF expression Mutational
Burden (HLA-DRA) deficiency status Pattern of distant PD-L1
expression PD-L1 expression on PTEN loss metastases infiltrating
leukocytes Quantity of ROR2 STAT1 expression T reg cell %
neoantigen peptides TAGLN TCR clonality TGFbeta level TIL number in
tumor TWIST2 VEGF level VEGFA aCTLA4 Absolute CD8+ cell number
CXCL11 expression CXCL9 expression therapy lymphocyte count CXCR3
expression Dendritic cell number EOMES + CD8+ cells FOXP3+ cells
number number IDO expression LDH expression M1 macrophage M1/M2
macrophage number ratio MDSC % Mutational Burden NY-ESO-1
seropostive PTEN loss T reg cell % TCR clonality TGFbeta level TIL
number in tumor VEGF level IL-2 therapy Bone metastasis concomitant
regional Leucocytes number LNPEP expression lymphadenopathy
C-reactive protein Delta32 CCR5 BCAT2 expression BDNFOS level
Polymorphism expression IL-10 (-1082G->A) CAIX expression
LOC130576 CCR5 LOF polymorphism expression mutation ERCC1 (codon
118) IFN-g (+874A->T) LOC399900 ATP6V0A2 polymorphism
polymorphism expression expression Ki-67 expression Alkaline
phosphatase ARHGAP10 CD56+ or CD57+ level expression cells number
Liver metastasis CD83+ TIDC cells cDNA FLJ37989 LDH level number
expression Fibronectin level HLA-DQB1 GBF1 expression amount of
alveolar expression component Albumin level clear cell FOXP3+ cells
number HLA-DQA1 histology expression granular features MAP3K5
expression MDSC number Mediastinum metastasis MEF2A expression
MTUS1 expression Neutrophil number NK cell number non clear cell
NR1H2 expression NRAS mutations Number of histology metastatic
sites papillary features PH-4 expression Platelets Number RABL2B
expression RC3H2 expression rs12553173 Sedimentation rate SUPT6H
expression TACC1 expression TDP1 expression TFPI expression Time
from tumor to occurrence of metastases Transferrin level TSH level
VCAM1 expression VEGF level Weight loss .alpha.-antitrypsin level
IFNa CAIX level Delta32 CCR5 Leucocytes count LNPEP expression
therapy Polymorphism ERCC1 (codon 118) GBF1 expression Bone
metastasis Breslow thickness polymorphism IL-6 expression CCR5 LOF
mutation LOC130576 CD4+ cells number level expression Hepatic RIG-1
IL-1.beta. expression LOC399900 BDNFOS expression level expression
expression Interval from initial ARHGAP10 BCAT2 expression CD8+
CD57+ cells diagnosis to expression number treatment Liver
metastasis CD83+ TIDC cells cDNA FLJ37989 fis Ki-67 expression
number expression HLA-Cw06 allele IL-1.alpha. expression HLA-DQB1
ATP6V0A2 level expression expression Alkaline collagen IV level
HLA-DQA1 IL-10 (-1082G->A) phosphatase level expression
polymorphism IFN-g (+874A->T) MAP3K5 expression Mediastinum
metastasis MEF2A expression polymorphism MIP-1.alpha. expression
MIP-1.beta. expression MTAP gene expression MTUS1 expression level
level Neutrophil count NR1H2 expression Number of metastatic
Osteopontin level sites Performance status PH-4 expression
Platelets Number RABL2B expression RC3H2 expression Sedimentation
rate Serum calcium level Serum hemoglobin level STAT1 gene SUPT6H
expression TACC1 expression TDP1 expression expression TFPI
expression Time from tumor to TNF-.alpha. expression level TRAIL
level occurrence of metastases Ulceration of VCAM1 expression VEGF
level VEGFR2 level primary Anti-cancer Cancer-Testis CD16+CD56+CD69
+ CD4+CD45RO+ cell CD4+CTLA-4+ T vaccine Antigens' Genes
lymphocytes number cell number therapy expression number CD4+PD-1+
T cell C-reactive protein ECOG performance EGF level number level
score I/II high-grade or III IFN-gamma-induced IgM for Blood Group
A IL-6 level T1/2/3a low-grade tumor cell apoptosis trisaccharide
level disease intermediate risk Intratumoral versus LDH level
Lin-CD14+HLA-DR-/lo lymphocyte number peritumoral T cell MDSC level
density lymphocytes in M1/M2 macrophage MDSC number Mean
Corpuscular PBMC % ratio Hemoglobin Concentration (MCHC) Number of
Patient's age Predictive gene PTEN loss CD27-CD45RA+ and signature
in MAGE A3 CD27-CD45RA- antigen-specific cancer and immunotherapy
CD27+CD45RA- T-cells Serum amyloid A Serum S100B Syndecan-4 mRNA T
reg cell % level concentration expression level TGFbeta level
Toll-like receptor 4 WT1 expression gene polymorphism Anti-
Acneiform rash Adrenomedullin angiopoietin-2 Bioactive Peptide
angiogenic Repeat expression levels Induced Signaling therapy
Polymorphism Pathway CD133 expression CDC16 level Child-Pugh class
CXCL10 plasma level CXCR1 rs2234671 CXCR2C785T CXCR2 rs2230054 ECOG
Performance G>C T>C Status EGF A-61G EGF rs444903 A>G EGFR
expression levels EGFR rs2227983 G>A Endothelin-1 Expression of
CD31 Expression of PDGFR- HBV status expression levels beta HGF
plasma level History of alcohol ICAM1 T469C IFN-.alpha.2 plasma
level intake IGF-1 rs6220 A>G IL-12 plasma level IL-16 plasma
level IL-2R.alpha. plasma level IL-3 plasma level IL-6 plasma level
IL-8 251 T>A IL-8 plasma level Lck and Fyn Liver metastasis
M-CSF plasma level mucinous histology tyrosine kinases in
initiation of TCR Activation pathway activation NO2-dependent IL
Number of resting Number of total PIGF plasma level 12 Pathway
circulating circulating endothelial activation in NK endothelial
cells cells cells portal vein rs12505758 in rs2286455 rs3130
thrombosis VEGFR2 rs699946 in VEGFA SDF-1.alpha. plasma level Sex
sVEGFR1 T Cell Receptor T Helper Cell Surface TRAIL plasma level
VEGF -1154 A>G Signaling Pathway Molecules expression activation
VEGF -1498 C>T VEGF C936T VEGF G-634C VEGF-1154 G/A VEGF-2578
C/A VEGFR1 rs9582036 VEGFR-2 rs2305948 WNK1-rs11064560 C>T
Rituximab BCL2 expression BCL6 expression Beclin-1 expression C1qA
Gene level Polymorphism Carbohydrate CD163-positive CD20 expression
CD37 expression antigen-125 level macrophages level CD5 expression
CXCR4 expression Cytotoxic T Fc.gamma.RIIIa 158H/H level level
lymphocyte-associated genotypes Granzyme B expression level
Galectin-1 HIP1R mRNA level IL-12 level IL-1RA level expression
Ki-67 expression MARCO expression Mast cell number 1 miR-155
expression MYC expression Number of p21 protein expression sLR11
level macrophages SMAD1 expression STAT3 T cells TAM number mRNA
level TIM3 expression
Calculating Normalized Biomarker Values
[0283] To analyze different parameters (e.g., T cell number, MHC
protein expression, BRAF mutation, etc.) or parameters for which
biomarker "threshold" values could not be clearly interpreted,
methods to normalize biomarker values were developed. Normalized
biomarker values are herein described in terms of "high," "medium"
and "low," where mathematically high values correspond to 1 and
mathematically low values correspond to -1.
[0284] Biomarkers with digital properties, such as certain
mutations (e.g., BRAFV600E), were normalized using a binary system,
where presence of a biomarker corresponded to 1, and absence of a
biomarker corresponded to 0. Biomarkers associated with protein
expression such as those determined from tissue staining
experiments, were assigned their corresponding gene expression
(e.g., target protein assigned target mRNA expression level).
Biomarkers associated with cellular composition in the tumor
microenvironment were recalculated with bioinformatics cell
deconvolution packages based on RNAseq data (e.g., MCPcounter,
CIBERSORT).
[0285] Normalized biomarker scores were calculated for a large
patient cohort in which patients were diagnosed based on their
tumor biopsy. Data was obtained from publicly available databases
of human cancer biopsies, and data was normalized for a particular
patient using one of the below formulas according to the
distribution of biomarker values calculated for the large patient
cohort.
[0286] Normalized parameter values in terms of "high" and "low"
were calculated based on the Z-score of the parameter value using
predefined mathematical functions where the normalized parameter
value ranges from -1 to 1 depending on Z-score. Mean and standard
deviation were taken from a previously calculated distribution of
parameter values for the large patient cohort to which the patient
belonged.
[0287] The function was set so that a zero value of the parameter
fell in the middle of the distribution, and the highest values were
assigned to parameters at the extreme upper end of the
distribution.
[0288] Unit step function a):
{ 1 , if Z - score value > C + cutoff 0 , if C - cutoff < Z -
score value < C + cutoff - 1 , if Z - score value < C -
cutoff ##EQU00001##
[0289] Where C.sup.+cutoff=normalized threshold value representing
a "high" parameter value, and C.sup.-cutoff=normalized threshold
value representing a "low" parameter value.
[0290] Or:
[0291] Flattened unit step function b):
{ | Z - score value | a | Z - score value | a + | C + cutoff | a ,
if Z - score value .gtoreq. 0 | Z - score value | a | Z - score
value | a + | C - cutoff | a , if Z - score value < 0
##EQU00002##
[0292] Where a>1=parameter defining the slope of the unit step
function. With a>.infin. function b) transforms to function
a).
[0293] Threshold value C.sup.+cutoff (C.sup.-cutoff) was equal to 1
(-1), indicating that 15% of patients had a high biomarker value,
and 15% of patients had a low biomarker value. Different cut-offs
may be used depending on the biomarkers involved in the
calculation.
[0294] After normalization, each biomarker was transformed to the
same range scale. Thus, a value equal to 1 represents a "high"
parameter value, and a value equal to -1 represents a "low"
parameter value. Parameter values equal or close to 0 reflect
median parameter values according to the distribution. A graphical
representation of biomarker value distribution for a large patient
cohort is shown in FIG. 3.
Defining Biomarker Significance
[0295] Biomarkers were assigned weights indicative of their
predictive significance based on whether the biomarker was obtained
from a large or small patient cohort. Biomarkers obtained from
studies using large patient cohorts may have higher predictive
significance, and therefore these biomarkers were assigned an
initial numeric weight of 3. Biomarkers obtained from studies using
small patient cohorts may have lower predictive significance, and
therefore these biomarkers were assigned an initial numeric weight
of 1.
[0296] Biomarkers were assigned weights indicative of their
predictive significance based on the role of the biomarker with
respect to a therapy. For example, when analyzing biomarkers for
treatment with an anti-PD1 therapy, PDL expression was a
significant biomarker that was assigned a higher numeric weight
than a less significant biomarker such as gender.
[0297] Biomarker significance in terms of "weight" was defined by
expert assessment or clinical studies where the biomarker was
identified. Significance or weight was based on clinical measures
(e.g., patient outcome) that split two cohorts of patients divided
by biomarker value. If the difference among clinical outcomes for a
biomarker was large (p-value<0.01), it was assigned a high
weight. If the clinical difference for a biomarker was minimal
(0.01<p-value<0.05), the biomarker weight was assigned a low
weight.
[0298] Alternatively or in addition to the foregoing, biomarker
significance was calculated for a biomarker within a set of
biomarkers using machine learning algorithms. This approach
involved extensive "training" of datasets. A set of biomarkers
obtained from literature was tested mathematically to improve
weights manually assigned to biomarkers. The algorithm provided a
list of significant biomarkers and insignificant biomarkers.
Insignificant biomarkers were excluded from the initial set without
loss of prediction accuracy.
Example 2: Therapy Scores Calculated from Biomarkers
[0299] Therapy scores were calculated for five patients using a sum
of normalized biomarker values multiplied by their "weight".
Patient 1 and Patient 2 had more positive biomarkers, and thus had
higher therapy scores (FIG. 4). Patient 4 had similar numbers of
positive and negative biomarkers and Patient 5 had biomarkers with
neutral values, and thus these patients had therapy scores of zero
(FIG. 4). Patient 3 had a greater number of negative biomarkers,
and thus has a negative therapy score (FIG. 4).
Example 3: Therapy Scores Predicted Treatment Response
[0300] Therapy scores for different therapies were calculated for a
non-responsive patient (Patient 1) and a responsive patient
(Patient 2) with respect to their response to the anti-PD1 therapy
Pembrolizumab. Based on the calculated therapy scores, Patient 1
was likely non-responsive to other treatments including anti-CTLA4
therapy, IL-2 therapy, vaccine therapy, and Bevacizumab (FIG. 5).
However, Patient 1's therapy score predicted a likely response to
IFN-.alpha. therapy (FIG. 5). Patient 2's therapy scores predicted
a likely response to each treatment. These results demonstrated
that therapy scores predicted both a response and a non-response to
a therapy.
[0301] Therapy scores were calculated as described herein for an
anti-PD1 therapy dataset and an anti-CTLA4 dataset. Patients
treated with an anti-PD1 therapy having higher therapy scores
calculated as a sum of positive and negative biomarkers were more
likely to respond to therapy, and patients with negative therapy
scores were unlikely to respond to therapy (FIG. 7A). Similar
results were obtained for patients treated with an anti-CTLA4
therapy (FIG. 7B).
[0302] Predictive accuracy was improved by using a prediction
cut-off. For example, analysis of the anti-PD1 therapy dataset
showed that the prediction rate was 73% when the non-response
cut-off was lower than zero and 88% when the non-response cut-off
was lower than -1 (FIG. 7C). Similarly, the prediction rate was 80%
when the response cut-off was higher than zero and improved to 91%
when the response cut-off was higher than 1 (FIG. 7C). Therapy
response rate predictions based on certain cut-offs for various
therapies are shown in Table 3.
TABLE-US-00003 TABLE 3 Therapy response rate prediction.
Non-response Pre- Response Pre- cut-off diction cut-off diction
Therapy (lower than) rate (higher than) rate aPD1 therapy 0 73% 0
80% aCTLA4 therapy -1 77% -- -- IFNa therapy 0 100% 0 70% MAGEA-3
vaccine -2 94% 0 50% Bevacizumab -1 80% 1 80% Rituximab Based -- --
0 100%
Example 4: Biomarker Weight Optimization Improved Therapy Score
Prediction Accuracy
[0303] Using an anti-PD1 therapy dataset obtained from Hugo et al.,
the prediction accuracy of therapy scores calculated with biomarker
weight optimization were compared to those calculated without
biomarker weight optimization. Therapy scores calculated without
biomarker weight optimization accurately predicted therapy response
for 73% of patients in the study (FIG. 8A). Calculating therapy
scores with biomarker weight optimization improved the prediction
rate to 85%. Biomarker weight optimization included calculating
feature importance using random forest regression, in which
abundant biomarkers were assigned higher importance for predicting
a therapy response (FIG. 8C). Biomarker weights were recalculated
with a logistic regression model to obtain the best prediction of
therapy response (FIG. 8D).
Example 5: Calculated Therapy Scores for Different Therapies
[0304] Different combinations of biomarkers were used for
calculating therapy scores for different therapies. Normalized
biomarker values for each patient treated with anti-PD1 therapy
(Table 4-5), aCTLA4 therapy (Table 6-7), IFN.alpha. therapy (Table
8), anti-cancer vaccine therapy (Table 9-10), and anti-angiogenic
therapy (Table 11) were calculated.
TABLE-US-00004 TABLE 4 Set of normalized biomarker values for each
patient having a negative therapy score treated with aPD1 therapy.
ID NO: 87 88 03 29.0 83 95 02 28.0 90 82 96 79 92 84 89 Response PD
PD PD PR PD PD PD PR PD PD PD PD CR MiR-BART9 expression 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Cancer gene
panels (CGPs) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 FM-CGP Cancer gene panels (CGPs) 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 HSL-CGP BRAF mutation 0.0 3.0
3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 0.0 3.0 0.0 3.0 STAT1
expression 0.0 0.0 -0.2 -0.2 -1.6 0.0 -1.0 -1.0 0.0 -0.4 0.0 0.2
0.0 -0.7 0.2 Granzyme B expression -0.2 0.0 0.0 0.0 -0.6 0.0 0.0
0.0 0.0 -0.9 0.0 0.0 0.0 0.0 0.4 Hugogene/AXL -0.5 -0.4 -0.2 -0.2
0.0 0.0 0.0 0.0 -0.5 0.4 0.0 0.0 0.0 0.4 -0.4 Hugogene/ROR2 -0.5
-0.3 -0.5 -0.5 0.0 -0.4 -0.4 -0.4 -0.1 0.0 -0.1 -0.5 0.0 -0.4 0.0
Hugogene/TAGLN -0.2 0.0 0.0 0.0 0.3 -0.5 -0.5 -0.5 -0.2 0.2 -0.4
-0.5 0.0 0.1 -0.5 Hugogene/TWIST2 -0.5 -0.2 0.0 0.0 -0.5 -0.4 -0.1
-0.1 -0.5 0.1 -0.3 -0.5 -0.5 0.0 0.0 Hugogene/CDH1 -2.8 -2.9 -2.4
-2.4 0.3 0.0 0.0 0.0 -2.9 1.6 -1.6 0.5 0.0 -2.5 -2.8 Hugogene/CCL2
0.0 -0.2 -0.4 -0.4 0.4 -0.3 -0.1 -0.1 -0.5 0.3 0.0 -0.3 -0.3 0.0
-0.5 Hugogene/CCL7 -0.3 0.0 0.0 0.0 0.0 0.0 -0.5 -0.5 -0.5 0.1 -0.5
0.0 -0.5 0.0 -0.5 Hugogene/CCL8 0.0 0.0 0.0 0.0 0.4 -0.3 -0.3 -0.3
-0.5 0.2 -0.5 0.0 -0.4 0.0 -0.4 Hugogene/CCL13 0.1 0.0 0.0 0.0 0.0
0.0 0.1 0.1 -0.5 0.0 0.0 -0.5 -0.5 0.3 -0.1 Hugogene/CVEGFC 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Hugogene/VEGFA
-0.9 0.0 0.0 0.0 0.0 0.0 0.1 0.1 -1.0 0.0 0.0 0.0 -0.2 -0.1 -1.0
EGFR expression 0.3 0.0 0.5 0.5 0.0 0.0 0.0 0.0 0.5 -0.2 0.0 0.2
0.0 0.0 0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 -1.5 -1.5 0.0
0.0 0.0 0.0 0.0 0.0 0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 B2M LOF mutation 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 LDH level -0.9 0.5
0.3 0.3 0.0 0.0 0.0 0.0 -0.9 0.0 0.8 0.0 -0.6 -0.8 -0.8
Pattern_of_distant_metastases 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 Lymphocyte number -1.3 -1.0 0.0 0.0 -2.3
0.0 0.0 0.0 -0.4 -2.4 -0.2 0.0 -0.1 -1.9 0.0 Eosinophil number 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Missmatch-repair deficiency 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 status PD-L1 expression -0.7 -0.6 -0.5 -0.5
-0.3 0.0 0.0 0.0 3.0 0.0 0.0 0.0 0.0 -0.1 0.1 TCR clonality -1.6
-0.6 0.0 0.0 -1.6 1.8 0.0 0.0 1.6 -1.6 0.0 -0.5 3.0 2.4 3.0
Quantity of neoantigen -0.2 -0.6 -0.2 -0.2 -0.2 -0.7 0.0 0.0 0.4
-0.1 -0.1 1.1 0.0 0.0 0.0 peptides Affinity of neontigens 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CXCR2
expression -0.5 0.0 -0.4 -0.4 -0.5 -0.3 0.0 0.0 0.0 0.0 -0.5 0.0
-0.5 0.0 0.0 ESRP1 expression 1.0 0.0 1.0 1.0 0.3 0.0 0.5 0.5 1.0
-0.1 0.0 0.0 0.5 1.0 1.0 MITF expression 0.8 0.5 0.9 0.9 -0.2 0.0
0.0 0.0 1.0 0.0 0.0 0.0 -0.2 0.0 0.6 Mutational Burden -0.1 -0.4
-0.1 -0.1 -0.1 -0.7 0.0 0.0 0.5 -0.1 -0.1 0.5 0.0 0.0 0.0 BRCA2
mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.0 0.0 0.0
0.0 CD8+ cell density in the -2.4 -2.2 0.0 0.0 -2.1 0.0 0.0 0.0
-0.1 -2.3 0.0 0.1 -0.7 -0.1 0.4 tumor invasive margin MHC-II
expression -2.6 0.0 0.0 0.0 0.0 0.0 -0.7 -0.7 0.0 -0.7 0.0 0.1 -0.1
-0.2 2.2 EGFR expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 CX3CL1 expression 0.3 -0.2 0.0 0.0 0.0 0.0 0.7
0.7 0.5 -1.0 0.7 -0.8 1.0 1.0 0.9 PD-L1 expression on -2.2 -1.7
-1.5 -1.5 -0.8 0.0 0.0 0.0 3.0 -0.1 0.0 0.0 0.0 -0.3 0.1
infiltrating leukocytes VEGF level -2.2 0.0 -0.8 -0.8 0.1 0.0 0.0
0.0 -3.0 0.0 0.0 -0.1 -1.8 0.0 -3.0 TGFbeta level -0.8 0.0 -3.0
-3.0 0.0 -2.9 0.0 0.0 -2.6 0.4 0.0 -1.4 0.0 0.0 -1.1 M1/M2
macrophage ratio -0.3 -0.1 -0.1 -0.1 -0.3 0.0 0.0 0.0 0.0 -0.3 0.0
0.0 -0.3 -0.1 0.0 T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 TIL number in tumor 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CD8+ cell number 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 M1 macrophage
number -2.4 -0.1 -0.2 -0.2 -2.4 0.3 0.0 0.0 0.0 -2.4 0.5 0.0 -2.4
0.0 1.4 Dendritic cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 Mutational Burden 0.0 -0.1 0.0 0.0 0.0 -0.2
0.0 0.0 0.5 0.0 0.0 0.5 0.0 0.0 0.0 TCR clonality 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.0 0.1 0.0
0.0 -0.3 0.0 -2.4 -2.4 0.0 0.8 0.0 1.5 1.6 -0.5 -0.2 Fibroblasts
-2.9 -2.0 -3.0 -3.0 0.0 -3.0 -2.4 -2.4 -3.0 0.3 -1.5 -2.9 0.0 0.0
-2.9 Endothelial cells -1.6 -0.2 -2.0 -2.0 0.0 -3.0 -0.1 -0.1 -3.0
0.0 -2.7 -3.0 -2.2 0.4 -0.1 Therapy Score -26.2 -9.9 -9.6 -9.6 -9.0
-7.5 -5.6 -5.6 -5.2 -5.0 -3.5 -3.4 -2.4 -2.0 -0.9 Abbreviations;
PR--partial response, SD--stable disease, CR--complete response,
and CPD--clinical progressive disease.
TABLE-US-00005 TABLE 5 Set of normalized biomarker values for each
patient having a positive therapy score treated with aPD1 therapy.
ID NO; 285 300 297 301 291 293 304 286 305 280 294 281 306 299 298
Response CR PR PD PD PR PR PR CR PR PR PD PR PR CR CR MiR-BART9
expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 Cancer gene panels 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 (CGPs) FM-CGP Cancer gene panels 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (CGPs) HSL-CGP BRAF
mutation 3.0 0.0 0.0 0.0 0.0 0.0 3.0 3.0 0.0 0.0 0.0 0.0 3.0 0.0
0.0 STAT1 expression -0.1 -2.5 0.0 0.0 0.0 -2.8 0.2 0.0 -1.1 0.3
1.1 0.0 1.1 0.3 2.0 Granzyme B expression -0.1 -0.5 0.0 0.0 0.0
-0.6 0.0 0.0 0.0 -0.3 0.8 0.0 1.0 0.0 0.0 Hugogene/AXL 0.0 0.4 0.0
0.0 0.0 0.4 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 -0.1 Hugogene/ROR2 0.0
0.0 0.2 0.0 0.2 0.0 0.0 0.0 0.2 0.3 0.0 0.2 0.0 0.0 0.0
Hugogene/TAGLN 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.4 0.1 0.1 0.0 -0.2
0.3 0.0 Hugogene/TWIST2 -0.2 -0.4 -0.5 0.0 0.0 0.0 0.0 -0.5 0.1 0.0
0.0 0.1 0.0 0.0 -0.3 Hugogene/CDH1 1.3 0.8 -2.9 -0.4 0.2 0.0 1.2
0.0 -2.1 1.4 -0.9 0.9 0.0 2.1 0.4 Hugogene/CCL2 -0.4 -0.1 0.0 0.0
0.0 0.0 0.0 0.0 0.5 0.0 -0.3 0.0 -0.1 0.0 0.0 Hugogene/CCL7 -0.4
-0.5 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.1 0.1 0.0
Hugogene/CCL8 -0.4 0.2 0.0 -0.4 -0.1 0.3 0.0 -0.3 0.3 0.0 -0.5 0.0
0.0 0.0 0.0 Hugogene/CCL13 -0.5 0.1 0.0 0.0 0.2 0.3 0.0 -0.5 0.3
0.2 -0.2 0.2 0.2 0.3 0.0 Hugogene/CVEGFC 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Hugogene/VEGFA 0.0 0.0 0.9 0.0
0.6 1.0 0.0 0.8 0.9 0.0 0.7 0.4 0.4 0.2 0.2 EGFR expression 0.0 0.5
0.0 0.0 0.0 -0.1 -0.1 0.1 -0.2 0.5 0.0 0.0 0.0 0.0 0.0 JAK1 LOF
mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -1.5 0.0 0.0
0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 B2M LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 LDH level 0.3 0.0 1.0 0.1 0.1 1.0 0.0
0.0 -0.3 0.1 0.0 0.0 0.2 -0.4 -0.6 Pattern_of_distant_metastases
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
Lymphocyte number -1.3 -0.1 0.0 0.0 0.0 -0.1 -0.1 0.0 0.0 -0.8 2.9
-0.1 3.0 -0.2 0.0 Eosinophil number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 Missmatch-repair 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 1.5 0.0 1.5 1.5 deficiency status PD-L1
expression 0.0 2.8 0.0 0.0 -0.1 -0.1 0.6 0.0 0.0 0.2 2.4 0.0 2.9
0.6 1.2 TCR clonality 0.0 -1.2 0.0 -0.9 0.1 0.0 -0.1 0.0 0.0 0.0
0.0 0.0 -0.6 0.0 2.6 Quantity of neoantigen 0.0 0.0 -0.5 -0.2 0.0
0.0 -0.1 0.0 0.0 2.4 0.0 3.0 -0.7 2.9 2.9 peptides Affinity of
neontigens 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 CXCR2 expression 0.0 -0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.5 0.0
-0.5 0.0 0.0 0.0 ESRP1 expression 0.0 -1.0 0.0 0.0 -0.1 0.4 -0.8
0.0 0.0 0.1 0.0 0.0 0.8 0.0 0.0 MITF expression 0.0 1.0 0.0 0.0 0.0
0.3 -0.5 0.0 0.0 0.0 -0.1 0.0 0.6 -0.7 -0.5 Mutational Burden 0.0
-0.1 -0.3 -0.2 0.0 0.0 -0.1 0.0 0.0 2.8 0.0 3.0 -0.5 2.7 2.7 BRCA2
mutation 0.0 3.0 0.0 0.0 0.0 3.0 0.0 0.0 0.0 0.0 0.0 3.0 0.0 3.0
3.0 CD8+ cell density in the 0.0 -1.4 0.7 1.0 0.0 0.0 0.0 0.1 0.0
0.0 3.0 -0.1 1.7 -0.1 0.0 tumor invasive margin MHC-II expression
0.0 -0.1 0.0 0.9 0.0 0.0 0.0 0.0 -0.1 0.0 2.5 0.0 2.4 0.0 0.9 EGFR
expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 CX3CL1 expression 0.2 0.9 0.0 1.0 1.0 0.0 -0.5 -0.2 -0.7 0.0
0.0 0.0 0.0 -0.6 -0.4 PD-L1 expression on 0.0 2.8 0.0 0.0 -0.2 -0.4
0.6 0.0 0.0 0.2 2.4 0.0 2.9 0.6 1.2 infiltrating leukocytes VEGF
level 0.0 0.0 2.8 0.0 2.1 3.0 0.0 2.6 2.9 0.0 1.3 2.5 0.0 0.9 0.2
TGFbeta level -0.6 0.1 2.1 0.0 0.2 0.0 0.0 0.0 2.9 0.0 0.7 0.0 -0.1
0.0 0.0 M1/M2 macrophage 0.0 -0.3 0.0 0.5 0.0 0.0 0.9 0.2 0.0 0.0
0.0 0.0 0.0 0.0 0.0 ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in tumor 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.9 0.0 0.0 CD8+ cell number 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 M1
macrophage 0.0 -2.4 0.0 3.0 0.0 0.0 3.0 2.8 0.0 0.3 0.0 0.8 -0.1
2.9 3.0 number Dendritic cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Mutational Burden 0.0 0.0 -0.1 -0.1
0.0 0.0 0.0 0.0 0.0 2.8 0.0 3.0 -0.2 2.7 2.7 TCR clonality 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.2
0.0 -0.2 0.0 -0.7 -2.3 0.0 0.0 0.0 0.0 0.0 0.0 0.6 2.8 2.5
Fibroblasts -0.2 0.0 0.1 0.0 0.6 0.0 0.0 -0.1 2.9 2.2 0.9 2.1 0.0
0.0 0.0 Endothelial cells -0.3 0.0 0.0 0.0 1.2 2.6 -1.2 -0.2 2.9
0.2 0.9 0.0 0.0 0.6 0.0 Therapy Score 0.8 1.4 3.5 4.4 5.3 5.6 6.1
7.9 10.2 12.4 17.6 18.5 20.0 22.6 25.1 Abbreviations; PR--partial
response, SD--stable disease, CR--complete response, and
CPD--clinical progressive disease.
TABLE-US-00006 TABLE 6 Set of normalized biomarker values for each
patient having a negative therapy score treated with aCTLA4
therapy. PD PD PD PD PD PD SD PD PD PD PD ID NO: 35 38 31 29 16 22
10 28 32 21 34 CXCL9 -0.9 -0.9 0.0 -0.8 -0.4 -0.9 -0.3 -0.9 -0.9
0.0 -0.9 expression CXCL11 -0.8 -0.7 0.0 1.0 -0.5 -0.5 -0.7 -0.2
-0.8 0.0 -0.8 expression CXCR3 0.0 -0.4 -0.4 -0.6 0.0 -0.7 0.8 -0.7
-0.7 0.0 -0.5 expression VEGF level -3.0 0.0 -2.8 0.0 0.0 0.0 -2.4
0.0 0.8 -1.2 2.2 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
FOXP3+ cells 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 number
Absolute 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 lymphocyte
count IDO -2.6 -1.9 -1.2 -2.3 -2.0 -0.7 -0.5 -0.6 -2.6 0.0 -2.5
expression NY-ESO-1 0.0 0.0 0.6 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0
seropostive EOMES+ CD8+ -0.3 -0.2 -0.2 -0.3 0.0 -0.3 0.0 -0.1 -0.3
0.0 -0.3 cells number LDH -0.2 0.0 0.0 0.0 0.0 0.1 0.2 0.0 0.0 -0.1
0.0 expression VEGF level 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 TGFbeta level -0.9 0.0 -0.3 -1.0 -0.8 0.0 -0.8 0.1 0.9 -0.6 0.2
M1/M2 0.0 -0.1 -0.1 -0.1 -0.1 0.0 -0.1 -0.2 -0.2 -0.1 -0.2
macrophage ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL
number in -2.3 -2.6 -0.3 -2.6 -1.4 -2.9 0.0 -1.9 -2.4 0.0 -2.8
tumor CD8+ cell -0.7 -0.7 -0.3 -0.1 0.0 -0.7 -0.2 -0.7 -0.5 -0.6
0.0 number M1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
macrophage number Dendritic cell 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 number Mutational 2.1 0.0 -0.1 -0.1 0.0 0.0 0.0 -0.1
0.0 0.0 0.0 Burden TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 PTEN loss 1.0 -0.4 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0
Therapy Score -8.6 -7.9 -5.1 -6.8 -5.3 -6.6 -3.3 -5.2 -5.7 -2.6
-5.7 PD PD CR SD PD PD PR PR PD SD ID NO: 30 36 4 13 26 41 5 6 37
11 CXCL9 0.6 0.0 -0.9 0.1 0.0 0.0 0.0 0.2 0.0 0.0 expression CXCL11
0.0 0.0 0.0 0.0 -0.1 0.0 0.0 0.1 -0.3 0.0 expression CXCR3 -0.2 0.0
-0.3 0.0 0.0 0.0 0.0 -0.3 0.0 -0.6 expression VEGF level -0.2 -1.1
0.0 -0.3 0.0 0.0 0.0 0.0 0.3 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 FOXP3+ cells 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0
number Absolute 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 lymphocyte
count IDO 0.0 -0.1 -0.1 0.0 0.0 -0.5 -1.1 0.0 0.0 0.0 expression
NY-ESO-1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 seropostive EOMES+
CD8+ 0.0 -0.2 0.0 0.0 0.0 0.0 0.0 0.0 -0.2 0.0 cells number LDH
-2.2 0.0 -0.1 -0.8 -0.2 0.0 0.0 -0.6 0.0 0.0 expression VEGF level
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TGFbeta level 0.0 0.0 0.0
0.0 -0.1 0.1 0.0 0.5 0.2 1.0 M1/M2 0.0 -0.1 -0.1 0.0 -0.1 0.0 0.0
0.2 0.0 0.0 macrophage ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL
number in 0.0 -0.1 -0.1 0.0 0.0 0.0 -0.5 -0.1 0.0 -0.5 tumor CD8+
cell -0.6 -0.7 0.0 0.0 -0.3 0.0 0.6 0.0 0.0 0.7 number M1 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 macrophage number Dendritic cell
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 number Mutational 0.0 0.0
0.0 0.0 -0.1 -0.1 0.0 0.0 0.0 0.0 Burden TCR clonality 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.0 0.0 0.0 -0.2 0.0 0.0 0.0
-0.1 0.0 -0.7 Therapy Score -2.6 -2.2 -1.6 -1.3 -0.8 -0.6 -0.9 0.0
-0.1 -0.2 Abbreviations; PR--partial response, SD--stable disease,
CR--complete response, and CPD--clinical progressive disease.
TABLE-US-00007 TABLE 7 Set of normalized biomarker values for each
patient having a positive therapy score treated with aCTLA4
therapy. PD PD SD PD PD CR PR PD PD PD PD PD PD PD SD PR PD SD PR
19 14 24 33 3 8 17 20 25 27 40 18 39 12 7 23 15 9 CXCL9 0.4 0.0 0.3
0.7 0.0 0.0 0.0 0.0 -0.8 0.7 1.0 0.9 0.3 0.9 0.7 0.0 1.0 0.0
expression CXCL11 0.0 -0.3 0.0 0.8 -0.8 0.0 0.7 0.0 0.0 0.1 0.7 0.5
0.0 0.8 0.3 0.0 0.9 1.0 expression CXCR3 0.0 -0.2 0.8 0.9 0.0 0.0
0.9 -0.3 0.0 0.4 1.0 0.1 0.9 1.0 0.8 0.0 0.8 0.0 expression VEGF
level 0.1 0.0 0.0 -0.6 -0.4 0.4 0.0 2.1 1.2 0.0 0.0 0.0 1.4 0.0 0.0
1.5 0.0 3.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 FOXP3+ cells 0.0 0.0 1.8 1.7 0.0 0.0 3.0
0.0 0.0 0.0 2.9 1.2 0.0 2.0 1.1 0.0 0.0 0.0 number Absolute 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
lymphocyte count IDO 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0 1.0 1.0
0.0 0.2 0.9 0.9 0.0 1.0 0.9 expression NY-ESO-1 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 1.0 1.0 0.0 1.0 0.0 0.0 0.0 0.3 0.0 0.0 seropositive
EOMES+ 0.0 -0.1 0.0 0.8 0.0 0.0 0.2 0.0 0.0 1.0 1.0 0.0 0.4 1.0 0.6
0.0 1.0 0.0 CD8+ cells number LDH 0.0 0.0 0.0 0.1 0.0 0.0 0.3 0.0
0.2 -2.8 0.1 0.0 0.0 0.4 -0.3 0.0 -0.2 3.0 expression VEGF level
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 TGFbeta level -0.1 0.0 -0.2 -0.9 0.0 0.8 0.0 0.8 0.0 0.5 -0.9
0.0 0.3 -0.2 0.0 0.9 0.9 1.0 M1/M2 0.0 -0.1 0.0 0.0 -0.1 0.0 0.0
-0.2 0.0 0.9 0.4 0.7 0.9 1.0 0.0 0.9 1.0 -0.2 macrophage ratio T
reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in 0.0 -0.1 1.3 0.4 2.9 0.0
2.9 0.0 0.0 0.0 2.8 0.0 0.7 2.9 1.8 0.0 2.6 0.3 tumor CD8+ cell 0.1
0.1 0.0 0.0 0.0 0.0 -0.3 0.0 1.0 0.9 0.6 0.0 1.0 1.0 0.9 0.0 1.0
0.0 number M1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 macrophage number Dendritic cell 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 number
Mutational 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -0.1 0.1 0.0 0.0 -0.1
0.2 3.0 3.0 2.8 0.0 Burden TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss -0.3 0.8
0.0 0.0 -0.4 0.0 0.0 -0.7 0.0 0.0 0.0 0.9 0.0 0.0 0.0 0.0 -0.2 1.0
Therapy Score 0.2 0.1 3.9 4.0 1.3 1.2 7.7 1.9 2.6 3.7 10.5 5.3 6.1
11.9 9.7 6.8 12.6 10.0 Abbreviations; PR--partial response,
SD--stable disease, CR--complete response, and CPD--clinical
progressive disease.
TABLE-US-00008 TABLE 8 Set of normalized biomarker values for each
patient treated with IFN.alpha. therapy. TCGA FR- FS- FS- D3- FW-
FS- YG- EB- FW- A7U8 A1ZS A4F0 A2JP A3TV A1ZW AA3O A6QY A3R5
Response PR SD SD PR SD PR CR CR CR ID: 847 4526 2367 1812 411 1505
1154 382 1124 ID NO: 10 16 19 9 13 18 11 4 6 Delta32 CCR5 0 0 0 0 0
0 0 0 0 Polymorphism CCR5 LOF 0 0 0 0 0 0 0 0 0 mutation IFN-g 0 0
0 0 0 0 0 0 0 (+874A->T) polymorphism IL-10 0 0 0 0 0 0 0 0 0
(-1082G->A) polymorphism ERCC1 0 0 0 0 0 0 0 0 0 (codon 118)
polymorphism VCAM1 -0.8 -0 -0.8 1 -0 0 -0 -0.5 0 expression
Platelets Number 0 0 0 0 0 0 0 0 0 Alkaline 0 0 0 0 0 0 0 0 0
Phosphatase level Sedimentation 0 0 0 0 0 0 0 0 0 rate Weight loss
0 0 0 0 0 0 0 0 0 Time from tumor 0 0 0 0 0 0 0 0 0 to occurrence
of metastases Number of 0 0 0 0 0 0 0 0 0 metastatic sites Bone
metastasis 0 0 0 0 0 0 0 0 0 Liver metastasis 0 0 0 0 0 0 0 0 0
Mediastinum 0 0 0 0 0 0 0 0 0 metastasis GBF1 expression 0.5 -0.5
-0.4 0.5 -0 0.3 -0.2 -0.1 -0.3 LNPEP -0.4 0.5 0.5 -0 0.5 -0 0 0 -0
expression MAP3K5 -0.4 0.5 0 -0 -0 -0.2 0 0 -0 expression cDNA
FLJ37989 0 0 0 0 0 0 0 0 0 fis expression RABL2B 0 0 -0 0.3 -0.3
0.4 -0.5 -0.1 0 expression MEF2A -0 0.5 0.2 -0 0 0 -0 0 0.2
expression LOC399900 0 0 0 0 0 0 0 0 0 expression HLA-DQA1 -0.2
-0.4 -0.1 0 0 -0.2 -0 -0.5 -0 expression TDP1 expression 0 0.5 0
-0.5 0.4 0 0 -0 0.4 RC3H2 -0 0.4 0 -0.3 0 -0 0.2 -0 0.3 expression
MTUS1 -0 -0 0 0.5 0 -0 0 -0 0 expression NR1H2 0.1 -0 -0.3 0 0 0.5
0 0 -0 expression SUPT6H 0 -0.5 -0.4 0 -0.1 0.3 -0 -0 0.3
expression BCAT2 -0 -0 -0.5 -0 0 0.5 -0 -0 -0 expression LOC130576
0 0 0 0 0 0 0 0 0 expression PH-4 expression 0.2 -0.4 0.3 -0 -0.5
0.1 0.3 -0 0.1 ARHGAP10 -0.5 0.1 0.4 0 0 -0.1 -0 -0 0.3 expression
TACC1 -0.5 0.5 -0 0 0.5 -0.2 0.4 0 0.3 expression HLA-DQB1 -0.4 -0
-0.4 0 -0 -0 -0 -0.1 -0 expression ATP6V0A2 -0.4 0.1 0.2 -0.4 0.5
-0 0.4 0.5 0.2 expression TFPI expression -0.3 0 -0 -0 -0 -0 -0 -0
0 BDNFOS 0 0 0 0 0 0 0 0 0 expression HLA-Cw06 allele 0 0 0 0 0 0 0
0 0 IL-1.alpha. expression -0 -0 -0 -0 -0 -0 -0 2 -0 level
IL-1.beta. expression -0.1 -0.1 -2.1 -0.9 -1.5 -0 -0.1 -0 -0.1
level IL-6 expression -1.2 0.4 -2.4 -0 -1.5 0.1 -0.7 -1.5 0.1 level
TNF-.alpha. expression -1.5 -1.6 -0.8 -1 -0.1 -0 -0 -0 -0.2 level
MIP-1.alpha. -0 -0.2 -2.8 0 -2.1 -0.2 -0.1 -1.4 -0 expression level
(CCL3) MIP-1.beta. -2 -0.2 -2.7 0.6 -0 0 -0 -0 0 expression level
(CCL4) Performance 0 0 0 0 0 0 0 0 0 status Interval from 0 0 0 0 0
0 0 0 0 initial diagnosis to treatmen Serum calcium 0 0 0 0 0 0 0 0
0 level Serum 0 0 0 0 0 0 0 0 0 hemoglobin level Osteopontin level
-0 -0 2.9 -2.9 -0 -1.2 0 0 -0 (SPP1) TRAIL level -1.8 0 -0 0 -0 0
-0.1 0.3 0 (TNFSF10) VEGFR2 level 1.5 0 -0 0.4 0 0.2 -0.1 0.4 -0
(KDR) VEGF level -1 0.1 -0 0.4 -0 0 0 0 -0 CAIX level -0.3 -0 0.5 0
-0 -1.6 0.6 -0 0.6 (CA9) collagen IV level 0 0 -0 0.2 -0.2 1.7 0
0.2 0 (COL4A1; COL4A2; COL4A3; COL4A4; COL4A5) Ulceration of 0 0 0
0 0 0 0 0 0 primary Breslow thickness 0 0 0 0 0 0 0 0 0 STAT1 gene
-0 0.1 2.4 -0 -0 0.4 -0.2 -0 0 expression MTAP gene -0 -2.9 1.4 -0
0.4 0 2.2 0.9 2.1 expression Ki-67 expression 0.3 -0 0 1.3 2.3 -0 0
-0 -2.9 (MKI67) Neutrophil count 0 0 0 0 0 0 0 0 0 Leucocytes count
-2.7 -0.8 -0.8 -0 0 0.2 -0 -0.1 0 CD8+ CD57+ -2.4 -1.5 -2.2 0 0 0
-0 -1 -0 cells number CD4+ cells -2.6 -1.9 -0 0 0.6 -0.8 0 -0 0.3
number CD83+ TIDC cells -1.9 -3 0.8 -2.9 0 0 0 2.9 2.9 number
Hepatic RIG-1 0 0 0 0 0 0 0 0 0 expression (DDX58) Therapy Score
-19 -10 -7.2 -3.6 -1 0.2 2.2 2 4.5 TCGA EB- FS- W3- ER- GN- D3- FR-
HR- A5SH A1ZT AA1Q A19M A4U5 A8GB A44A A2OH Response SD CPD CPD CR
CR CR CR CR ID: 1643 1617 2101 1857 1156 938 5299 2004 ID NO: 3 17
14 12 7 2 5 8 Delta32 CCR5 0 0 0 0 0 0 0 0 Polymorphism CCR5 LOF 0
0 0 0 0 0 0 0 mutation IFN-g 0 0 0 0 0 0 0 0 (+874A->T)
polymorphism IL-10 0 0 0 0 0 0 0 0 (-1082G->A) polymorphism
ERCC1 0 0 0 0 0 0 0 0 (codon 118) polymorphism VCAM1 -0 0 0.9 0.6 0
0 0.7 0.5 expression Platelets Number 0 0 0 0 0 0 0 0 Alkaline 0 0
0 0 0 0 0 0 Phosphatase level Sedimentation 0 0 0 0 0 0 0 0 rate
Weight loss 0 0 0 0 0 0 0 0 Time from tumor 0 0 0 0 0 0 0 0 to
occurrence of metastases Number of 0 0 0 0 0 0 0 0 metastatic sites
Bone metastasis 0 0 0 0 0 0 0 0 Liver metastasis 0 0 0 0 0 0 0 0
Mediastinum 0 0 0 0 0 0 0 0 metastasis GBF1 expression -0.4 -0 0.3
0 0 0.5 -0 -0 LNPEP -0.5 -0 -0 0 0 -0.2 0 0 expression MAP3K5 -0.5
-0 0 0 0 -0 0.5 0 expression cDNA FLJ37989 0 0 0 0 0 0 0 0 fis
expression RABL2B -0 -0.3 0.2 -0.1 0 0 0.1 0 expression MEF2A -0.5
0 -0.2 0.1 -0 -0.2 0.3 0 expression LOC399900 0 0 0 0 0 0 0 0
expression HLA-DQA1 -0 -0 0.1 -0 0.4 -0 0.5 0.3 expression TDP1
expression -0 0 -0.1 0.3 -0 -0.4 -0 0 RC3H2 -0 0.3 -0 0 -0 -0.4 0.1
0.1 expression MTUS1 -0.4 -0 -0.5 0.1 0 -0.2 0 0.4 expression NR1H2
-0.1 0.4 0 -0 -0 0 0 -0 expression SUPT6H 0 -0 0.5 0 -0 0.4 0 -0
expression BCAT2 -0 0.1 0.5 0 0 -0 0.4 0 expression LOC130576 0 0 0
0 0 0 0 0 expression PH-4 expression 0.5 -0 0.5 0.3 -0 -0 -0 -0
ARHGAP10 -0.5 0.4 -0 -0.1 -0 0 -0 -0 expression TACC1 0 -0.1 -0.1
-0 -0 -0.1 0 0 expression HLA-DQB1 -0 -0 0 0.4 0.4 0 0.5 0.5
expression ATP6V0A2 -0.5 0 -0 0.2 -0 -0.3 0 -0 expression TFPI
expression -0.5 -0 -0.4 -0 -0 0 -0 -0 BDNFOS 0 0 0 0 0 0 0 0
expression HLA-Cw06 allele 0 0 0 0 0 0 0 0 IL-1.alpha. expression
-0 -0 -0 -0 0.3 -0 -0 -0 level IL-1.beta. expression -0.1 0 -1.4 -0
-0 -0 0 0 level IL-6 expression -1.4 0.9 -0 -0 -0 2.8 -0.1 0.2
level TNF-.alpha. expression -0 0 -0.2 -0.2 0 -0 0 0.1 level
MIP-1.alpha. -0 -0 -2.8 0 0 1.3 2.9 2.9 expression level (CCL3)
MIP-1.beta. -0.9 0 -0 2.5 2.3 1 3 3 expression level (CCL4)
Performance 0 0 0 0 0 0 0 0 status Interval from 0 0 0 0 0 0 0 0
initial diagnosis to treatmen Serum calcium 0 0 0 0 0 0 0 0 level
Serum 0 0 0 0 0 0 0 0 hemoglobin level Osteopontin level 3 0.2 2.9
-1.6 -0 0 -0 0.3
(SPP1) TRAIL level -1.9 0 -0 1 1.2 0 1.8 2 (TNFSF10) VEGFR2 level 0
0 -0 0 1.2 0.3 0.1 0.1 (KDR) VEGF level 1.4 0 0.2 -0 1.4 0.3 0 0
CAIX level 0.6 -0 0.6 -0 -0 0 0.2 -0 (CA9) collagen IV level 1 0
1.9 0 0 -0 0 0.4 (COL4A1; COL4A2; COL4A3; COL4A4; COL4A5)
Ulceration of 0 0 0 0 0 0 0 0 primary Breslow thickness 0 0 0 0 0 0
0 0 STAT1 gene -3 0.5 -0 2.7 2.2 -0 2.9 2.9 expression MTAP gene 0
0.9 0.2 -2.8 -2.7 -0 -2.5 0 expression Ki-67 expression 2.8 0 3
-0.9 0.6 2.9 0 -0.9 (MKI67) Neutrophil count 0 0 0 0 0 0 0 0
Leucocytes count 0 1.8 -0 -0 -0 2.7 1 2.7 CD8+ CD57+ -0 0.3 0 2.5
2.1 0.9 2.9 3 cells number CD4+ cells 0 1 2.6 2.7 2.7 0 0.3 3
number CD83+ TIDC cells 1.5 -0.3 -1.7 0.4 0 0 0 -0 number Hepatic
RIG-1 0 0 0 0 0 0 0 0 expression (DDX58) Therapy Score -0.4 6.4 7
8.1 12 11 16 21 Abbreviations; PR--partial response, SD--stable
disease, CR--complete response, and CPD--clinical progressive
disease.
TABLE-US-00009 TABLE 9 Set of normalized biomarker values for each
patient having a negative therapy score treated with anti-cancer
vaccine therapy. Response NR NR NR NR NR NR NR NR R NR NR NR NR NR
NR NR NR NR R R NR R R R NR ID NO: 21 33 17 5 26 34 25 22 65 27 3
14 19 20 28 35 4 15 51 52 2 58 54 66 32 TGFbeta level -0.05 2.13
-2.99 0.01 0 -0.17 0 0.36 1.42 -0.03 0.93 0.31 0 1.08 -2.91 0 0
1.57 -0 0.91 0.88 0.19 -0.83 -0.15 1.02 M1/M2 macrophage ratio -0
-0 -0 -0 -0 -0 -0 -0 1 -0 1 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0
-0 T reg cell % 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
MDSC number 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
lymphocyte number -2.75 -2.76 -2.44 -1.24 -1.33 -0.07 -2.64 -0.09
-2.34 -2.74 -1.06 -2.64 0.04 -0.87 -0 -0.01 -0.51 -0.01 0.08 -0.09
-1.48 -0 0 -0.01 -0 ECOG performance 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 score EGF level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 Cancer-Testis Antigens' 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 Genes expression IFN-gamma-induced 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tumor cell apoptosis IL-6
level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Mean
Corpuscular 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 Predictive gene signature 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 in MAGE A3 antigen- specific
cancer immunotherapy TGFbeta1 level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 CD16+ CD56+ CD69+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 lymphocytes number CD4+ PD-1+ T cell -1.37 0 -0
-0 -2.07 -0.07 0 -0.01 2.37 -1.19 -0.09 0.01 0.01 -1.08 -0 0.01 -0
-0.44 0.64 -1.78 0 -0.92 0 -2.52 -1.73 number_1 C-reactive protein
level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Intratumoral versus -2.82 -4.02 -4.13 -4.13 -4.55 -2.25 -4.02 -3.26
-3.45 -4.06 -3.12 -2.97 -0.12 -0.69 -0.01 -0.45 -0.03 -2.17 0.38
-1.34 -0.01 -0 -0.12 -0 0 peritumoral T cell density Serum amyloid
A level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Toll-like
receptor 4 gene 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
polymorphism Syndecan-4 mRNA 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade
disease_intermediate risk lymphocytes in PBMC % -0.92 -0.92 -0.81
-0.41 -0.44 -0.02 -0.88 -0.03 -0.78 -0.91 -0.35 -0.88 0.01 -0.29 -0
-0 -0.17 -0 0.03 -0.03 -0.49 -0 0 -0 -0 PTEN loss -0.89 0.94 0
-0.96 1 0.98 0.01 -0 -0.13 1 0.13 0.15 -0.02 -0.52 0 -0.49 0.69
0.01 -0 0.38 0.86 -0.89 -0.01 -0.95 -0 CD4+ CD45RO+ cell 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 number Number of CD27- 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27-
CD45RA- and CD27+ CD45RA- T-cells CD4+ CTLA-4+ T cell 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 number CD4+ PD-1+ T cell 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood
Group A 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
trisaccharide level Lin-CD14+ HLA-DR-/lo 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 MDSC level B2M -2.93 -2.56 0.08 -0 -0.08
-2.54 0 -2.25 -0.22 0.79 -0.5 -0.04 -2.42 0 -0 0.04 0 0 -2.94 0.53
-0.93 0.15 0.01 1.33 0.21 CD86 -2.93 -2.53 -0.39 -2.78 -0.68 -2.91
-1.37 -0 -2.98 -0.43 -2.32 -1.09 -1.27 -0.11 -0.6 -2.18 -0.34 0
-0.25 -0 -0.04 0.03 -0 -0 0 CXCL10 -2.92 -2.91 -1.62 -2.27 -2.96
-2.92 -0.35 -2.72 -2.48 0.01 -1.97 -0 -0.98 -0.12 -0 -0.07 -1.92 -0
0 0 -0.08 0.14 0 1.61 0.03 CXCL9 -2.76 -2.93 -2.93 -2.93 -2.91
-2.93 -1.94 -2.9 -1.66 0 -0.03 -0 -0.02 -1.05 0 -0.08 -0.35 -0.8
0.26 -0.01 -0 0.01 -0 0.23 0.06 Therapy Score -20.3 -15.6 -15.2
-14.7 -14 -12.9 -11.2 -10.9 -9.25 -7.56 -7.39 -7.15 -4.75 -3.65
-3.52 -3.23 -2.63 -1.84 -1.81 -1.43 -1.31 -1.3 -0.95 -0.46 -0.42
Abbreviations; PR--partial response, SD--stable disease,
CR--complete response, and CPD--clinical progressive disease.
TABLE-US-00010 TABLE 10 Set of normalized biomarker values for each
patient having a positive therapy score treated with anti-cancer
vaccine therapy. Response NR NR R R R NR NR R NR NR R NR NR R R NR
NR ID NO: 29 8 55 63 59 11 12 62 7 18 45 13 31 49 64 23 10 TGFbeta
level 0.01 0 0.01 -1.7 0.04 1.42 -1.57 1.25 0.53 -0.27 -0.45 -0.12
1.42 -0.04 0.38 -2.69 0 M1/M2 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0
-0 -0 -0 -0 -0 macrophage ratio T reg cell % 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
lymphocyte 0.06 0.29 0.16 -0 0.31 -0 0.93 -0 0.06 0.21 0.12 0.11 0
0.41 0 0.22 2.37 number ECOG 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
performance score EGF level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Cancer-Testis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Antigens' Genes
expression IFN-gamma- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 induced
tumor cell apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Mean Corpuscular 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin
Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 Predictive gene 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 signature in
MAGE A3 antigen-specific cancer immunotherapy TGFbeta1 level 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 CD16+ CD56+ CD69+ 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 lymphocytes number CD4+ PD-1+ T cell 0 -0.06 -0.38 -0.3
0 -0.7 0.02 -0.04 -1.09 2.07 2.77 -0.19 1.64 -0 -0.66 -0.01 2.7
number_1 C-reactive protein 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 level
Intratumoral -0 1.84 0 0 0 0.23 0 -0 0.04 0.01 0.15 0 -0 0.11 0.46
0.86 4.69 versus peritumoral T cell density Serum amyloid A 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 level Toll-like receptor 4 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 gene polymorphism Syndecan-4 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 mRNA expression level WT1 expression 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 I/II
high-grade or III 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a
low-grade disease_intermediate risk lymphocytes in 0.02 0.1 0.05 -0
0.1 -0 0.31 -0 0.02 0.07 0.04 0.04 0 0.14 0 0.07 0.79 PBMC % PTEN
loss 0 0 0 -0.57 -0 0.45 -0 0 -0.29 -0.08 0.02 -0.01 -0.02 0 -0
0.42 -0 CD4+ CD45RO+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 cell number
Number of CD27- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27-
CD45RA- and CD27+ CD45RA- T-cells CD4+ PD-1+ T cell 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 number_1 IgM for Blood 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 Group A trisaccharide level Lin-CD14+ HLA- 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 DR-/lo MDSC level B2M -0.01 -2.93 0.01 0.5 0.31
-1.13 0.02 0 0.69 0.19 0 0.05 0.02 0.66 1.74 0.83 -3 CD86 -0.02
0.05 0.01 0.72 0 0.44 1.75 0.19 -0 0.04 0.25 0.05 0.76 0 1.15 1.53
-0.03 CXCL10 -0 0 0.44 1.82 0.01 0.03 -0.25 0 1.13 0.28 -0.01 1.75
0.05 2.09 1.65 2.32 -0.81 CXCL9 -0.01 1.22 0.53 0.48 0.22 0.41 -0
-0 0.62 0.04 0 1.5 0 1.52 0.87 2.09 0 Therapy Score 0.05 0.5 0.83
0.95 1 1.17 1.21 1.39 1.7 2.55 2.87 3.16 3.87 4.88 5.59 5.64 6.71
Response R NR R R NR R R NR NR R R R R NR ID NO: 61 16 56 48 24 50
46 6 9 47 57 53 60 30 TGFbeta level 0.22 2 -1.34 -0.23 1.42 0.49 -0
-2.9 -1.05 0.04 0.26 -0 0.08 -0 M1/M2 -0 -0 -0 -0 -0 -0 -0 -0 -0 -0
-0 -0 -0 -0 macrophage ratio T reg cell % 0 0 0 0 0 0 0 0 0 0 0 0 0
0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 0 0 0 lymphocyte 1.58 0 -0 2.99
2.87 1.64 0.01 0.12 2.74 0 2.96 2.92 2.63 2.68 number ECOG 0 0 0 0
0 0 0 0 0 0 0 0 0 0 performance score EGF level 0 0 0 0 0 0 0 0 0 0
0 0 0 0 Cancer-Testis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Antigens' Genes
expression IFN-gamma- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 induced tumor
cell apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Mean
Corpuscular 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration
(MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Predictive gene 0
0 0 0 0 0 0 0 0 0 0 0 0 0 signature in MAGE A3 antigen-specific
cancer immunotherapy TGFbeta1 level 0 0 0 0 0 0 0 0 0 0 0 0 0 0
CD16+ CD56+ CD69+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 lymphocytes number
CD4+ PD-1+ T cell -0 0 0 3 -0 -1.39 0 -0 2.99 2.62 2.8 -2.52 0 3
number_1 C-reactive protein 0 0 0 0 0 0 0 0 0 0 0 0 0 0 level
Intratumoral 2.59 0.75 0.08 4.99 2.83 0.42 3.69 4.17 4.65 0 4.93
4.89 4.69 4.43 versus peritumoral T cell density Serum amyloid A 0
0 0 0 0 0 0 0 0 0 0 0 0 0 level Toll-like receptor 4 0 0 0 0 0 0 0
0 0 0 0 0 0 0 gene polymorphism Syndecan-4 0 0 0 0 0 0 0 0 0 0 0 0
0 0 mRNA expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 0 0
0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 0 0 0 concentration LDH level 0
0 0 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0
0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes
in 0.53 0 -0 1 0.96 0.55 0 0.04 0.91 0 0.99 0.97 0.88 0.89 PBMC %
PTEN loss 0.66 -0.08 0.99 -0.83 -0 0 -0.41 -0.02 0 -0 -0.65 0 -0.02
-0.36 CD4+ CD45RO+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 cell number Number
of CD27- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27- CD45RA- and
CD27+ CD45RA- T-cells CD4+ PD-1+ T cell 0 0 0 0 0 0 0 0 0 0 0 0 0 0
number_1 IgM for Blood 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Group A
trisaccharide level Lin-CD14+ HLA- 0 0 0 0 0 0 0 0 0 0 0 0 0 0
DR-/lo MDSC level B2M 0.15 1.36 2.61 -2.95 0.02 2.61 1.78 2 -2.38
2.12 0 1.29 2.27 0.02 CD86 0 0.41 1.28 0.55 1.36 2.04 2.27 2.53 2.7
2.35 1.79 2.84 2.2 2.89 CXCL10 0.13 1.63 2.78 -0 0.03 2.26 2.38
2.57 0.16 2.51 -0 2.08 2.24 2.76 CXCL9 0.98 1.85 1.66 0.19 0.04
2.02 1.04 2.26 1.25 2.37 0.02 2.27 2.02 2.18 Therapy Score 6.85
7.92 8.06 8.71 9.52 10.6 10.8 10.8 12 12 13.1 14.7 17 18.5
Abbreviations; PR--partial response, SD--stable disease,
CR--complete response, and CPD--clinical progressive disease.
TABLE-US-00011 TABLE 11 Set of normalized biomarker values for each
patient treated with anti-angiogenic therapy. Patient ID GSM14718
39 86 53 58 75 42 82 71 47 Response: NR NR NR NR R R NR R R
Timepoint: PT PT PT PT PT PT PT PT PT Number of resting 0.000162
-1.97328 -0.00283 -1.3E-06 -0.67291 -0.97508 -0.68776 -0.00018
0.533442 circulating endothelial cells Number of total 0 0 0 0 0 0
0 0 0 circulating endothelial cells Expression of -2.97683 -0.00033
-0.00618 -0.69032 0.001726 0.000607 0.004197 -1.29847 -0.18186
PDGFR-beta Expression of 0 0.570456 0.000747 1.482181 0 2.460252
1.408502 0.000326 0 CD31 CDC16 level -9.4E-07 -0.11814 -1.60473
1.244301 -0.09602 3.4E-05 -1.0432 -0.02895 -1.6E-07 Lck and Fyn
-0.96874 0.730858 -0.38819 -0.14019 1.06E-06 -0.18482 1.58E-05
0.00172 0.002242 tyrosine kinases in initiation of TCR Activation
pathway activation T Cell Receptor 0 0 0 0 0 0 0 0 0 Signaling
Pathway activation T Helper Cell 0 0 0 0 0 0 0 0 0 Surface
Molecules expression NO2-dependent 0 0 0 0 0 0 0 0 0 IL 12 Pathway
activation in NK cells Bioactive Peptide 0 0 0 0 0 0 0 0 0 Induced
Signaling Pathway sVEGFR1 -2.99459 -0.2038 1.932855 0.000431
-0.01157 -0.33766 -2.89576 1.5E-08 0.310332 CD133 0 0 0 0 0 0 0 0 0
expression rs2286455 0 0 0 0 0 0 0 0 0 rs3130 0 0 0 0 0 0 0 0 0
IL-6 plasma level 0 0 0 0 0 0 0 0 0 IL-8 plasma level 0 0 0 0 0 0 0
0 0 Child-Pugh class 0 0 0 0 0 0 0 0 0 HBV status 0 0 0 0 0 0 0 0 0
portal vein 0 0 0 0 0 0 0 0 0 thrombosis Sex 0 0 0 0 0 0 0 0 0
History of alcohol 0 0 0 0 0 0 0 0 0 intake Acneiform rash 0 0 0 0
0 0 0 0 0 angiopoietin-2 -8.4E-11 -0.81987 -0.2002 -2.53227
0.001005 -2.10171 -2.94843 -0.12168 3.27E-06 expression levels EGFR
expression -0.98928 -0.34509 1.07E-06 -0.00033 0.045048 0.098944
0.934068 0.009977 0.068077 levels Endothelin-1 0.754617 -4.3E-08
-0.02217 -0.73196 0.198087 -0.00242 -0.03232 0.002418 0.170778
expression levels angiopoietin-2 0 0 0 0 0 0 0 0 0 expression
levels IL-12 plasma 0 0 0 0 0 0 0 0 0 level HGF plasma level 0 0 0
0 0 0 0 0 0 IL-16 plasma 0 0 0 0 0 0 0 0 0 level CXCL10 plasma 0 0
0 0 0 0 0 0 0 level SDF-1.alpha. plasma 0 0 0 0 0 0 0 0 0 level
IL-2R.alpha. plasma 0 0 0 0 0 0 0 0 0 level IL-3 plasma level 0 0 0
0 0 0 0 0 0 IFN-.alpha.2 plasma 0 0 0 0 0 0 0 0 0 level TRAIL
plasma 0 0 0 0 0 0 0 0 0 level M-CSF plasma 0 0 0 0 0 0 0 0 0 level
PIGF plasma 0 0 0 0 0 0 0 0 0 level mucinous 0 0 0 0 0 0 0 0 0
histology VEGF-1498C > T 0 0 0 0 0 0 0 0 0 Liver metastasis 0 0
0 0 0 0 0 0 0 ECOG 0 0 0 0 0 0 0 0 0 Performance Status VEGF-1154 A
> G 0 0 0 0 0 0 0 0 0 VEGF G-634C 0 0 0 0 0 0 0 0 0 ICAM1 T469C
0 0 0 0 0 0 0 0 0 WNK1- 0 0 0 0 0 0 0 0 0 rs11064560 EGF A-61G 0 0
0 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 0 0 0 VEGF-1154 G/A 0 0 0 0 0
0 0 0 0 VEGF-2578 C/A 0 0 0 0 0 0 0 0 0 rs699946 in 0 0 0 0 0 0 0 0
0 VEGFA rs12505758 in 0 0 0 0 0 0 0 0 0 VEGFR2 VEGFR1 0 0 0 0 0 0 0
0 0 rs9582036 EGF rs444903 0 0 0 0 0 0 0 0 0 A > G IGF-1 rs6220
0 0 0 0 0 0 0 0 0 A > G CXCR1 0 0 0 0 0 0 0 0 0 rs2234671 G >
C CXCR2 0 0 0 0 0 0 0 0 0 rs2230054 T > C EGFR rs2227983 0 0 0 0
0 0 0 0 0 G > A VEGFR-2 0 0 0 0 0 0 0 0 0 rs2305948 C > T
IL-8 251 T > A 0 0 0 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 0 0 0
VEGF C936T 0 0 0 0 0 0 0 0 0 Adrenomedullin 0 0 0 0 0 0 0 0 0
Repeat Polymorphism VEGFA 0 0 0 0 0 0 2.259422 1.028465 1.81E-10
ICAM1 -0.27451 0.000147 -1.3524 -1.2E-09 -0.35542 0.304107 2.516688
-3.6E-12 -0.9676 Therapy Score -7.44919 -2.15904 -1.64309 -1.36816
-0.89005 -0.73775 -0.48458 -0.40637 -0.06459 Patient ID GSM14718 50
64 67 60 80 74 77 55 Response: NR NR NR R R NR R R Timepoint: PT PT
PT PT PT PT PT PT Number of resting -0.00749 0.873339 -1.67907
0.143095 -1.93425 1.318883 -1.7134 1.698203 circulating endothelial
cells Number of total 0 0 0 0 0 0 0 0 circulating endothelial cells
Expression of -0.38181 0.00909 -0.26866 -0.0735 -4.8E-09 0.14841
1.195321 1.614482 PDGFR-beta Expression of 3.95E-05 0 3.95E-05 0
2.986855 0 0 2.741311 CD31 CDC16 level -0.04842 -0.0615 1.26E-06
3.4E-05 0.850735 1.787078 0.080641 1.974031 Lck and Fyn 1.33E-09
-3.5E-06 0.097905 2.49E-08 0.949367 -0.4284 0.082804 -0.98781
tyrosine kinases in initiation of TCR Activation pathway activation
T Cell Receptor 0 0 0 0 0 0 0 0 Signaling Pathway activation T
Helper Cell 0 0 0 0 0 0 0 0 Surface Molecules expression
NO2-dependent 0 0 0 0 0 0 0 0 IL 12 Pathway activation in NK cells
Bioactive Peptide 0 0 0 0 0 0 0 0 Induced Signaling Pathway sVEGFR1
0.974816 0.592048 0.241733 1.68231 -2.93689 -2.7E-10 -6.2E-08
-0.0023 CD133 0 0 0 0 0 0 0 0 expression rs2286455 0 0 0 0 0 0 0 0
rs3130 0 0 0 0 0 0 0 0 IL-6 plasma level 0 0 0 0 0 0 0 0 IL-8
plasma level 0 0 0 0 0 0 0 0 Child-Pugh class 0 0 0 0 0 0 0 0 HBV
status 0 0 0 0 0 0 0 0 portal vein 0 0 0 0 0 0 0 0 thrombosis Sex 0
0 0 0 0 0 0 0 History of alcohol 0 0 0 0 0 0 0 0 intake Acneiform
rash 0 0 0 0 0 0 0 0 angiopoietin-2 -0.24052 0.360074 1.61E-14
0.000457 -0.42763 0.000343 -0.00322 -2.97733 expression levels EGFR
expression 0.001253 0.515136 -0.98413 0.017333 0.376318 -0.27847
-0.92899 -0.08396 levels Endothelin-1 -2.7E-06 0.890757 0.707517
0.085635 -0.39897 0.077677 -0.99431 -0.94965 expression levels
angiopoietin-2 0 0 0 0 0 0 0 0 expression levels IL-12 plasma 0 0 0
0 0 0 0 0 level HGF plasma level 0 0 0 0 0 0 0 0 IL-16 plasma 0 0 0
0 0 0 0 0 level CXCL10 plasma 0 0 0 0 0 0 0 0 level SDF-1.alpha.
plasma 0 0 0 0 0 0 0 0 level IL-2R.alpha. plasma 0 0 0 0 0 0 0 0
level IL-3 plasma level 0 0 0 0 0 0 0 0 IFN-.alpha.2 plasma 0 0 0 0
0 0 0 0 level TRAIL plasma 0 0 0 0 0 0 0 0 level M-CSF plasma 0 0 0
0 0 0 0 0 level PIGF plasma 0 0 0 0 0 0 0 0 level mucinous 0 0 0 0
0 0 0 0 histology VEGF-1498C > T 0 0 0 0 0 0 0 0 Liver
metastasis 0 0 0 0 0 0 0 0 ECOG 0 0 0 0 0 0 0 0 Performance Status
VEGF-1154 A > G 0 0 0 0 0 0 0 0 VEGF G-634C 0 0 0 0 0 0 0 0
ICAM1 T469C 0 0 0 0 0 0 0 0 WNK1- 0 0 0 0 0 0 0 0 rs11064560 EGF
A-61G 0 0 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 0 0 VEGF-1154 G/A 0 0
0 0 0 0 0 0 VEGF-2578 C/A 0 0 0 0 0 0 0 0 rs699946 in 0 0 0 0 0 0 0
0
VEGFA rs12505758 in 0 0 0 0 0 0 0 0 VEGFR2 VEGFR1 0 0 0 0 0 0 0 0
rs9582036 EGF rs444903 0 0 0 0 0 0 0 0 A > G IGF-1 rs6220 0 0 0
0 0 0 0 0 A > G CXCR1 0 0 0 0 0 0 0 0 rs2234671 G > C CXCR2 0
0 0 0 0 0 0 0 rs2230054 T > C EGFR rs2227983 0 0 0 0 0 0 0 0 G
> A VEGFR-2 0 0 0 0 0 0 0 0 rs2305948 C > T IL-8 251 T > A
0 0 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 0 0 VEGF C936T 0 0 0 0 0 0
0 0 Adrenomedullin 0 0 0 0 0 0 0 0 Repeat Polymorphism VEGFA 0
0.007774 0 0 4.64E-06 0.182942 2.982064 0 ICAM1 -0.00017 -2.45837
2.727169 -0.06574 2.997447 0.000147 2.144079 -0.00516 Therapy Score
0.297699 0.728342 0.84251 1.789627 2.462987 2.808607 2.844987
3.021824 Abbreviations; NR--no response, PR--partial response,
SD--stable disease, CR--complete response, and CPD--clinical
progressive disease.
REFERENCES
[0305] Hugo et al., Genomic and Transcriptomic Features of Response
to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 165, 35-44
(2016). [0306] Van Allen et al., Genomic Correlates of Response to
CTLA-4 Blockade in Metastatic Melanoma. Science. 350(6257):302-22
(2015).
Illustrative Embodiments
[0307] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information, a normalized score for each
biomarker in at least a subject subset of the plurality of
biomarkers to obtain a set of normalized biomarker scores for the
subject, wherein the subject subset of the plurality of biomarkers
is a subset of the reference subset of the plurality of biomarkers;
and determining, using the set of normalized biomarker scores for
the subject, therapy scores for the plurality of therapies, each of
the therapy scores indicative of predicted response of the subject
to administration of a respective therapy in the plurality of
therapies.
[0308] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker
in at least a reference subset of a plurality of biomarkers across
a respective group of people, each of the plurality of biomarkers
being associated with at least one therapy in a plurality of
therapies; determining, using the sequencing data and the biomarker
information, a normalized score for each biomarker in at least a
subject subset of the plurality of biomarkers to obtain a set of
normalized biomarker scores for the subject, wherein the subject
subset of the plurality of biomarkers is a subset of the reference
subset of the plurality of biomarkers; and determining, using the
set of normalized biomarker scores for the subject, therapy scores
for the plurality of therapies, each of the therapy scores
indicative of predicted response of the subject to administration
of a respective therapy in the plurality of therapies.
[0309] In one aspect provided herein is a method, comprising using
at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker in at least
a reference subset of a plurality of biomarkers across a respective
group of people, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information, a normalized score for each biomarker in at least a
subject subset of the plurality of biomarkers to obtain a set of
normalized biomarker scores for the subject, wherein the subject
subset of the plurality of biomarkers is a subset of the reference
subset of the plurality of biomarkers; and determining, using the
set of normalized biomarker scores for the subject, therapy scores
for the plurality of therapies, each of the therapy scores
indicative of predicted response of the subject to administration
of a respective therapy in the plurality of therapies.
[0310] In some embodiments, the plurality of biomarkers includes a
first biomarker, and determining a normalized score for each
biomarker in at least the subject subset of the plurality of
biomarkers comprises: determining a first normalized score for the
first biomarker using the distribution of values for the first
biomarker. In some embodiments, determining the first normalized
score comprises: determining a first un-normalized score for the
first biomarker using the sequencing data; determining a first
Z-score based on the first distribution of values for the first
biomarker; and determining the first normalized score for the first
biomarker based on the first un-normalized score and the first
Z-score.
[0311] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies as a sum of two
or more scores in the set of normalized biomarker scores for the
subject.
[0312] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies at least in part
by: determining weights for two or more scores in the set of
normalized biomarker scores for the subject; and determining the
first therapy score as a weighted sum of the two or more scores,
summands of the sum being weighted by the determined weights.
[0313] In some embodiments, determining the weights comprises
determining the weights using a statistical model. In some
embodiments, determining the weights comprises determining the
weights using a generalized linear model. In some embodiments,
determining the weights comprises determining the weights using a
logistic regression model.
[0314] In some embodiments, the plurality of therapies comprises a
first therapy and a second therapy different from the first
therapy, and wherein determining therapy scores for the plurality
of therapies comprises: determining a first therapy score for the
first therapy using a first subset of the set of normalized
biomarker scores for the subject; and determining a second therapy
score for the second therapy using a second subset of the set of
normalized biomarker scores for the subject, wherein the second
subset is different from the first subset.
[0315] Some embodiments include providing the determined therapy
scores to a user. Some embodiments include ranking the plurality of
therapies based on the determined therapy scores. Some embodiments
include recommending at least one of the plurality of therapies for
the subject based on the determined therapy scores.
[0316] In some embodiments, recommending the at least one of the
plurality of therapies comprises: ranking the plurality of
therapies based on the determined therapy scores; and recommending
at least a threshold number of top-ranked therapies for the
subject.
[0317] In some embodiments, the plurality of therapies comprises at
least two therapies selected from the group consisting of: an
anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN
alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy.
[0318] In some embodiments, the plurality of biomarkers associated
with the anti-PD1 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-PD1
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-PD1 therapy in Table 2.
[0319] In some embodiments, the plurality of biomarkers associated
with the anti-CTLA4 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CTLA4
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-CTLA4 therapy in Table 2.
[0320] In some embodiments, the plurality of biomarkers associated
with the IL-2 therapy comprises at least three biomarkers selected
from the group of biomarkers associated with IL-2 therapy in Table
2. In some embodiments, determining the normalized biomarker scores
for the subject comprises determining a normalized score for each
of at least three biomarkers selected from the group of biomarkers
associated with IL-2 therapy in Table 2.
[0321] In some embodiments, the plurality of biomarkers associated
with the IFN alpha therapy comprises at least three biomarkers
selected from the group of biomarkers associated with IFN alpha
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with IFN alpha therapy in Table 2.
[0322] In some embodiments, the plurality of biomarkers associated
with the anti-cancer vaccine therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2. In some embodiments,
determining the normalized biomarker scores for the subject
comprises determining a normalized score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2.
[0323] In some embodiments, the plurality of biomarkers associated
with the anti-angiogenic therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2. In some embodiments,
determining the normalized biomarker scores for the subject
comprises determining a normalized score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2.
[0324] In some embodiments, the plurality of biomarkers associated
with the anti-CD20 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CD20
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-CD20 therapy in Table 2. In some
embodiments, the anti-CD20 therapy is rituximab.
[0325] Some embodiments further include generating a graphical user
interface (GUI) comprising: a first portion associated with a first
therapy in the plurality of therapies, the first portion including
a first plurality of GUI elements, each of the first plurality of
GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the first set of normalized scores; and a
second portion associated with a second therapy in the plurality of
therapies, the second portion including a second plurality of GUI
elements different from the first plurality of GUI elements, each
of the second plurality of GUI elements being associated with a
respective biomarker in the plurality of biomarkers and having at
least one visual characteristic determined based on a normalized
score of the respective biomarker in the second set of normalized
scores; and displaying the generated GUI.
[0326] In some embodiments, the at least one visual characteristic
comprises color of a GUI element and/or size of the GUI
element.
[0327] In some embodiments, in response to receiving, via the GUI,
a user selection of the first therapy, presenting, via the GUI,
information about at least one biomarker with which at least one of
the first plurality of GUI elements is associated.
[0328] In some embodiments, the first therapy is associated with a
first therapy score and the second therapy is associated with a
second therapy score, and wherein the first portion and the second
portion are positioned, relative to one another in the GUI, based
on relative magnitude of the first therapy score and the second
therapy score.
[0329] In some embodiments, each of the plurality of biomarkers is
selected from the group consisting of: a genetic biomarker, a
cellular biomarker, a saccharide biomarker, a lipid biomarker, a
heterocyclic biomarker, an elementary compound biomarker, an
imaging biomarker, an anthropological biomarker, a personal habit
biomarker, a disease-state biomarker, and an expression biomarker.
In some embodiments, the one or more genetic biomarkers includes a
gene or marker described in the description and/or the figures.
[0330] In some embodiments, one or more genetic biomarkers are
selected from the group consisting of: interferons, cytotoxic
proteins, enzymes, cell adhesion proteins, extracellular matrix
proteins and polysaccharides, cell growth factors, cell
differentiation factors, transcription factors, and intracellular
signaling proteins. In some embodiments, the one or more genetic
biomarkers is selected from the group consisting of: a cytokine, a
chemokine, a chemokine receptor, and an interleukin. In some
embodiments, the value of one or more cellular biomarkers is
determined through analysis of the number of one or more types of
cells or the percentage of one or more types of cells within the
biological sample. In some embodiments, the one or more types of
cells are selected from the group consisting of malignant cancerous
cells, leukocytes, lymphocytes, stromal cells, vascular endothelial
cells, vascular pericytes, and myeloid-derived suppressor cells
(MDSCs). In some embodiments, the value of one or more expression
biomarkers is determined through analysis of the expression level
or enzymatic activity of the nucleic acid or protein of the
expression biomarker.
[0331] In some embodiments, the sequencing data is one or more of:
DNA sequencing data, RNA sequencing data, or proteome sequencing
data. In some embodiments, the sequencing data is obtained using
one or more of the following techniques: whole genome sequencing
(WGS), whole exome sequencing (WES), whole transcriptome
sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray,
DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP)
genotyping.
[0332] In some embodiments each of the at least one biological
samples is a bodily fluid, a cell sample, a liquid biopsy, or a
tissue biopsy. In some embodiments, the tissue biopsy comprises one
or more samples from one or more tumors or tissues known or
suspected of having cancerous cells.
[0333] In some embodiments, the biomarker information also
comprises results from one or more of the following types of
analyses: blood analysis, cytometry analysis, histological
analysis, immunohistological analysis, and patient history
analysis.
[0334] In some embodiments, each of the therapies are selected from
the group consisting of: surgery, radiation therapy, chemotherapy,
immunotherapy, viral therapy, targeted therapy, hormone therapy,
transplants, phototherapy, cryotherapy, and hyperthermia. In some
embodiments, each of the therapies are selected from immunotherapy
and targeted therapy.
[0335] In some embodiments, the therapy scores are indicative of
response of the subject to administration of one therapy in the
plurality of therapies. In some embodiments, the therapy scores are
indicative of predicted response of the subject to administration
of multiple therapies in the plurality of therapies.
[0336] In one aspect provided herein is a system comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining first sequencing data about at
least one biological sample of a subject prior to administration of
a candidate therapy; obtaining second sequencing data about at
least one other biological sample of the subject subsequent to
administration of the candidate therapy; accessing, in the at least
one database, biomarker information indicating a distribution of
values for each biomarker, across a respective group of people, in
at least a reference subset of a plurality of biomarkers;
determining, using the first and second sequencing data and the
biomarker information, a first set of normalized biomarker scores
for the subject and a second set of normalized biomarker scores for
the subject; and determining, using the first and second sets of
normalized biomarker scores for the subject, an impact score for
the candidate therapy, wherein the impact score is indicative of
response of the subject to administration of the candidate
therapy.
[0337] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining first sequencing data about at least one
biological sample of a subject prior to administration of a
candidate therapy; obtaining second sequencing data about at least
one other biological sample of the subject subsequent to
administration of the candidate therapy; accessing, in at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of a plurality of biomarkers; determining,
using the first and second sequencing data and the biomarker
information, a first set of normalized biomarker scores for the
subject and a second set of normalized biomarker scores for the
subject; and determining, using the first and second sets of
normalized biomarker scores for the subject, an impact score for
the candidate therapy, wherein the impact score is indicative of
response of the subject to administration of the candidate
therapy.
[0338] In one aspect provided herein is a method, comprising: using
at least one computer hardware processor to perform: obtaining
first sequencing data about at least one biological sample of a
subject prior to administration of a candidate therapy; obtaining
second sequencing data about at least one other biological sample
of the subject subsequent to administration of the candidate
therapy; accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker, across a
respective group of people, in at least a reference subset of a
plurality of biomarkers; determining, using the first and second
sequencing data and the biomarker information, a first set of
normalized biomarker scores for the subject and a second set of
normalized biomarker scores for the subject; and determining, using
the first and second sets of normalized biomarker scores for the
subject, an impact score for the candidate therapy, wherein the
impact score is indicative of response of the subject to
administration of the candidate therapy.
[0339] In some embodiments, determining the impact score for the
candidate therapy further comprises: determining, using the first
and second sets of normalized biomarker scores, a difference score
for each biomarker in at least a subject subset of the plurality of
biomarkers to obtain a set of biomarker difference scores for the
subject; and determining, using the set of biomarker difference
scores, the impact score for the candidate therapy.
[0340] In some embodiments, determining the impact score for the
candidate therapy further comprises: determining, using the first
and second sets of normalized biomarker scores, a first and second
subject subset score for the subject subset of the plurality of
biomarkers determining a subject subset difference score, wherein
the subject subset difference score is determined using the first
and second subject subset score; and determining, using the subject
subset difference score, the impact score for the candidate
therapy.
[0341] In some embodiments, the candidate therapy is selected from
the group consisting of: an anti-PD1 therapy, an anti-CTLA4
therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer
vaccine therapy, an anti-angiogenic therapy, and an anti-CD20
therapy.
[0342] In some embodiments, the plurality of biomarkers associated
with the anti-PD1 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-PD1
therapy in Table 2.
[0343] In some embodiments, determining the biomarker difference
scores for the subject comprises determining a difference score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-PD1 therapy in Table 2.
[0344] In some embodiments, determining the subject subset
difference score for the subject comprises determining a first and
second subject subset score for at least three biomarkers selected
from the group of biomarkers associated with anti-PD1 therapy in
Table 2.
[0345] In some embodiments, the plurality of biomarkers associated
with the anti-CTLA4 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CTLA4
therapy in Table 2. In some embodiments, determining the biomarker
difference scores for the subject comprises determining a
difference score for each of at least three biomarkers selected
from the group of biomarkers associated with anti-CTLA4 therapy in
Table 2. In some embodiments, determining the subject subset
difference score for the subject comprises determining a first and
second subject subset score for at least three biomarkers selected
from the group of biomarkers associated with anti-CTLA4 therapy in
Table 2.
[0346] In some embodiments, the plurality of biomarkers associated
with the IL-2 therapy comprises at least three biomarkers selected
from the group of biomarkers associated with IL-2 therapy in Table
2. In some embodiments, determining the biomarker difference scores
for the subject comprises determining a difference score for each
of at least three biomarkers selected from the group of biomarkers
associated with IL-2 therapy in Table 2. In some embodiments,
determining the subject subset difference score for the subject
comprises determining a first and second subject subset score for
at least three biomarkers selected from the group of biomarkers
associated with IL-2 therapy in Table 2.
[0347] In some embodiments, the plurality of biomarkers associated
with the IFN alpha therapy comprises at least three biomarkers
selected from the group of biomarkers associated with IFN alpha
therapy in Table 2. In some embodiments, determining the biomarker
difference scores for the subject comprises determining a
difference score for each of at least three biomarkers selected
from the group of biomarkers associated with IFN alpha therapy in
Table 2. In some embodiments, determining the subject subset
difference score for the subject comprises determining a first and
second subject subset score for at least three biomarkers selected
from the group of biomarkers associated with IFN alpha therapy in
Table 2.
[0348] In some embodiments, the plurality of biomarkers associated
with the anti-cancer vaccine therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2. In some embodiments,
determining the biomarker difference scores for the subject
comprises determining a difference score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2. In some embodiments,
determining the subject subset difference score for the subject
comprises determining a first and second subject subset score for
at least three biomarkers selected from the group of biomarkers
associated with anti-cancer vaccine therapy in Table 2.
[0349] In some embodiments, the plurality of biomarkers associated
with the anti-angiogenic therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2. In some embodiments,
determining the biomarker difference scores for the subject
comprises determining a difference score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2. Ins ome embodiments,
determining the subject subset difference score for the subject
comprises determining a first and second subject subset score for
at least three biomarkers selected from the group of biomarkers
associated with anti-angiogenic therapy in Table 2.
[0350] In some embodiments, the plurality of biomarkers associated
with the anti-CD20 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CD20
therapy in Table 2. In some embodiments, wherein determining the
biomarker difference scores for the subject comprises determining a
difference score for at least three biomarkers selected from the
group of biomarkers associated with anti-CD20 therapy in Table 2.
In some embodiments, wherein determining the subject subset
difference score for the subject comprises determining a first and
second subject subset score for at least three biomarkers selected
from the group of biomarkers associated with anti-CD20 therapy in
Table 2. In some embodiments, the anti-CD20 therapy is
rituximab.
[0351] Some embodiments include generating a graphical user
interface (GUI) comprising a first portion associated with the
candidate therapy, the first portion including a first plurality of
GUI elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a difference score of the respective biomarker; and
displaying the generated GUI.
[0352] Some embodiments include generating a graphical user
interface (GUI) comprising: a first portion associated with the
candidate therapy, the first portion including a first plurality of
GUI elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a subject subset difference score; and displaying the
generated GUI. In some embodiments, the at least one visual
characteristic comprises color of a GUI element and/or size of the
GUI element. Some embodiments include, in response to receiving,
via the GUI, a user selection of the candidate therapy, presenting,
via the GUI, information about at least one biomarker with which at
least one of the first plurality of GUI elements is associated.
[0353] In some embodiments, determining the difference score for
each biomarker in at least the subject subset comprises:
determining a first normalized score for a first biomarker using
the first sequencing data; determining a second normalized score
for the first biomarker using the second sequencing data; and
determining a first difference score based on a difference between
the first and second normalized scores.
[0354] In some embodiments, determining the difference score for
each biomarker in at least the subject subset comprises:
determining a first subject subset score for at least three
biomarkers using the first sequencing data; determining a second
subject subset score for at least three biomarkers using the second
sequencing data; and determining a first subject subset difference
score based on a difference between the first and second subject
subset scores.
[0355] In some embodiments, the biomarker information includes a
first distribution of values for the first biomarker across a first
group of people, and wherein determining the first normalized score
comprises: determining a first un-normalized score for the first
biomarker using the first sequencing data; determining a first
Z-score based on the first distribution of values for the first
biomarker; and determining the first normalized score for the first
biomarker based on the first un-normalized score and the first
Z-score.
[0356] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information: a first set of normalized scores for
a first set of biomarkers associated with a first therapy in the
plurality of therapies; and a second set of normalized scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized scores as input to a statistical model to obtain
a first therapy score for the first therapy; providing the second
set of normalized scores as input to the statistical model to
obtain a second therapy score for the second therapy; generating a
graphical user interface (GUI), wherein the GUI comprises: a first
portion associated with a first therapy in the plurality of
therapies, the first portion including a first plurality of GUI
elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a normalized score of the respective biomarker in the
first set of normalized scores; and a second portion associated
with a second therapy in the plurality of therapies, the second
portion including a second plurality of GUI elements different from
the first plurality of GUI elements, each of the second plurality
of GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the second set of normalized scores; and
displaying the generated GUI.
[0357] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in at least one
database, biomarker information indicating a distribution of values
for each biomarker in at least a reference subset of a plurality of
biomarkers across a respective group of people, each of the
plurality of biomarkers being associated with at least one therapy
in a plurality of therapies; determining, using the sequencing data
and the biomarker information: a first set of normalized scores for
a first set of biomarkers associated with a first therapy in the
plurality of therapies; and a second set of normalized scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized scores as input to a statistical model to obtain
a first therapy score for the first therapy; providing the second
set of normalized scores as input to the statistical model to
obtain a second therapy score for the second therapy; generating a
graphical user interface (GUI), wherein the GUI comprises: a first
portion associated with a first therapy in the plurality of
therapies, the first portion including a first plurality of GUI
elements, each of the first plurality of GUI elements being
associated with a respective biomarker in the plurality of
biomarkers and having at least one visual characteristic determined
based on a normalized score of the respective biomarker in the
first set of normalized scores; and a second portion associated
with a second therapy in the plurality of therapies, the second
portion including a second plurality of GUI elements different from
the first plurality of GUI elements, each of the second plurality
of GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the second set of normalized scores; and
displaying the generated GUI.
[0358] In one aspect provided herein is a method, comprising using
the at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker in at least
a reference subset of a plurality of biomarkers across a respective
group of people, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information: a first set of normalized scores for a first set of
biomarkers associated with a first therapy in the plurality of
therapies; and a second set of normalized scores for a second set
of biomarkers associated with a second therapy in the plurality of
therapies, wherein the first set of biomarkers is different from
the second set of biomarkers; providing the first set of normalized
scores as input to a statistical model to obtain a first therapy
score for the first therapy; providing the second set of normalized
scores as input to the statistical model to obtain a second therapy
score for the second therapy; generating a graphical user interface
(GUI), wherein the GUI comprises: a first portion associated with a
first therapy in the plurality of therapies, the first portion
including a first plurality of GUI elements, each of the first
plurality of GUI elements being associated with a respective
biomarker in the plurality of biomarkers and having at least one
visual characteristic determined based on a normalized score of the
respective biomarker in the first set of normalized scores; and a
second portion associated with a second therapy in the plurality of
therapies, the second portion including a second plurality of GUI
elements different from the first plurality of GUI elements, each
of the second plurality of GUI elements being associated with a
respective biomarker in the plurality of biomarkers and having at
least one visual characteristic determined based on a normalized
score of the respective biomarker in the second set of normalized
scores; and displaying the generated GUI.
[0359] In some embodiments, the plurality of biomarkers includes a
first biomarker, and wherein determining a normalized score for
each biomarker in at least the subject subset of the plurality of
biomarkers comprises: determining a first normalized score for the
first biomarker using the distribution of values for the first
biomarker. In some embodiments, determining the first normalized
score comprises: determining an un-normalized score for the first
biomarker using the sequencing data; determining a Z-score based on
the first distribution of values for the first biomarker; and
determining a normalized score for the first biomarker based on the
un-normalized score and the Z-score.
[0360] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies as a sum of two
or more scores in the set of normalized biomarker scores for the
subject.
[0361] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies at least in part
by: determining weights for two or more scores in the set of
normalized biomarker scores for the subject; and determining the
first therapy score as a sum of the two or more scores, summands of
the sum being weighted by the determined weights. In some
embodiments, determining the weights comprises determining the
weights using a machine learning technique. In some embodiments,
determining the weights comprises determining the weights using a
generalized linear model. In some embodiments, determining the
weights comprises determining the weights using a logistic
regression model.
[0362] In some embodiments, the plurality of therapies comprises a
first therapy and a second therapy different from the first
therapy, and wherein determining therapy scores for the plurality
of therapies comprises: determining a first therapy score for the
first therapy using a first subset of the set of normalized
biomarker scores for the subject; and determining a second therapy
score for the second therapy using a second subset of the set of
normalized biomarker scores for the subject, wherein the second
subset is different from the first subset.
[0363] Some embodiments include recommending at least one of the
plurality of therapies for the subject based on the determined
therapy scores. Some embodiments include ranking the plurality of
therapies based on the determined therapy scores. In some
embodiments, recommending the at least one of the plurality of
therapies comprises: ranking the plurality of therapies based on
the determined therapy scores; and recommending at least a
threshold number of top-ranked therapies for the subject.
[0364] In some embodiments, the plurality of therapies comprise at
least two therapies selected from the group consisting of: an
anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN
alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy.
[0365] In some embodiments, the plurality of biomarkers associated
with the anti-PD1 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-PD1
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-PD1 therapy in Table 2.
[0366] In some embodiments, the plurality of biomarkers associated
with the anti-CTLA4 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CTLA4
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-CTLA4 therapy in Table 2.
[0367] In some embodiments, the plurality of biomarkers associated
with the IL-2 therapy comprises at least three biomarkers selected
from the group of biomarkers associated with IL-2 therapy in Table
2. In some embodiments, determining the normalized biomarker scores
for the subject comprises determining a normalized score for each
of at least three biomarkers selected from the group of biomarkers
associated with IL-2 therapy in Table 2.
[0368] In some embodiments, the plurality of biomarkers associated
with the IFN alpha therapy comprises at least three biomarkers
selected from the group of biomarkers associated with IFN alpha
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with IFN alpha therapy in Table 2.
[0369] In some embodiments, the plurality of biomarkers associated
with the anti-cancer vaccine therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2. In some embodiments,
determining the normalized biomarker scores for the subject
comprises determining a normalized score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-cancer vaccine therapy in Table 2.
[0370] In some embodiments, the plurality of biomarkers associated
with the anti-angiogenic therapy comprises at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2. In some embodiments,
determining the normalized biomarker scores for the subject
comprises determining a normalized score for each of at least three
biomarkers selected from the group of biomarkers associated with
anti-angiogenic therapy in Table 2.
[0371] In some embodiments, the plurality of biomarkers associated
with the anti-CD20 therapy comprises at least three biomarkers
selected from the group of biomarkers associated with anti-CD20
therapy in Table 2. In some embodiments, determining the normalized
biomarker scores for the subject comprises determining a normalized
score for each of at least three biomarkers selected from the group
of biomarkers associated with anti-CD20 therapy in Table 2. In some
embodiments, the anti-CD20 therapy is rituximab.
[0372] In some embodiments, the at least one visual characteristic
comprises color of a GUI element and/or size of the GUI
element.
[0373] In some embodiments, in response to receiving, via the GUI,
a user selection of the first therapy, presenting, via the GUI,
information about at least one biomarker with which at least one of
the first plurality of GUI elements is associated.
[0374] In some embodiments, the first therapy is associated with a
first therapy score and the second therapy is associated with a
second therapy score, and wherein the first portion and the second
portion are positioned, relative to one another in the GUI, based
on relative magnitude of the first therapy score and the second
therapy score.
[0375] In some embodiments, each of the plurality of biomarkers is
selected from the group consisting of: a genetic biomarker, a
cellular biomarker, a saccharide biomarker, a lipid biomarker, a
heterocyclic biomarker, an elementary compound biomarker, an
imaging biomarker, an anthropological biomarker, a personal habit
biomarker, a disease-state biomarker, and an expression
biomarker.
[0376] In some embodiments, the value of one or more genetic
biomarkers is determined through the identification of one or more
mutations, insertions, deletions, rearrangements, fusions, copy
number variations (CNV), or single nucleotide variants (SNV) in the
nucleic acid or protein of the genetic biomarker.
[0377] In some embodiments, the one or more genetic biomarkers
includes a gene or marker described in the description and/or the
figures.
[0378] In some embodiments, one or more genetic biomarkers are
selected from the group consisting of: interferons, cytotoxic
proteins, enzymes, cell adhesion proteins, extracellular matrix
proteins and polysaccharides, cell growth factors, cell
differentiation factors, transcription factors, and intracellular
signaling proteins.
[0379] In some embodiments, the one or more genetic biomarkers is
selected from the group consisting of: a cytokine, a chemokine, a
chemokine receptor, and an interleukin.
[0380] In some embodiments, the value of one or more cellular
biomarkers is determined through analysis of the number of one or
more types of cells or the percentage of one or more types of cells
within the biological sample.
[0381] In some embodiments, the one or more types of cells are
selected from the group consisting of malignant cancerous cells,
leukocytes, lymphocytes, stromal cells, vascular endothelial cells,
vascular pericytes, and myeloid-derived suppressor cells
(MDSCs).
[0382] In some embodiments, the value of one or more expression
biomarkers is determined through analysis of the expression level
or enzymatic activity of the nucleic acid or protein of the
expression biomarker.
[0383] In some embodiments, the sequencing data is one or more of:
DNA sequencing data, RNA sequencing data, or proteome sequencing
data. In some embodiments, the sequencing data is obtained using
one or more of the following techniques: whole genome sequencing
(WGS), whole exome sequencing (WES), whole transcriptome
sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray,
DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP)
genotyping.
[0384] In some embodiments, each of the at least one biological
samples is a bodily fluid, a cell sample, a liquid biopsy, or a
tissue biopsy. In some embodiments, the tissue biopsy comprises one
or more samples from one or more tumors or tissues known or
suspected of having cancerous cells.
[0385] In some embodiments, the biomarker information also
comprises results from one or more of the following types of
analyses: blood analysis, cytometry analysis, histological
analysis, immunohistological analysis, and patient history
analysis.
[0386] In some embodiments, each of the therapies are selected from
the group consisting of: surgery, radiation therapy, chemotherapy,
immunotherapy, viral therapy, targeted therapy, hormone therapy,
transplants, phototherapy, cryotherapy, and hyperthermia.
[0387] In some embodiments, each of the therapies are selected from
immunotherapy and targeted therapy.
[0388] In some embodiments, the therapy scores are indicative of
response of the subject to administration of one therapy in the
plurality of therapies. In some embodiments, the therapy scores are
indicative of response of the subject to administration of multiple
therapies in the plurality of therapies.
[0389] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of the plurality of biomarkers, each of
the plurality of biomarkers being associated with at least one
therapy in a plurality of therapies; determining, using the
sequencing data and the biomarker information: a first set of
normalized biomarker scores for a first set of biomarkers
associated with a first therapy in the plurality of therapies; and
a second set of normalized biomarker scores for a second set of
biomarkers associated with a second therapy in the plurality of
therapies, wherein the first set of biomarkers is different from
the second set of biomarkers; providing the first set of normalized
biomarker scores as input to a statistical model to obtain a first
therapy score for the first therapy; providing the second set of
normalized biomarker scores as input to the statistical model to
obtain a second therapy score for the second therapy; wherein the
plurality of therapies comprise at least two therapies selected
from the group consisting of: an anti-PD1 therapy, an anti-CTLA4
therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer
vaccine therapy, an anti-angiogenic therapy, and an anti-CD20
therapy, and wherein the plurality of biomarkers associated with
each of the plurality of therapies comprises at least three
biomarkers selected from the group of biomarkers associated with
the respective therapy in Table 2.
[0390] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker,
across a respective group of people, in at least a reference subset
of the plurality of biomarkers, each of the plurality of biomarkers
being associated with at least one therapy in a plurality of
therapies; determining, using the sequencing data and the biomarker
information: a first set of normalized biomarker scores for a first
set of biomarkers associated with a first therapy in the plurality
of therapies; and a second set of normalized biomarker scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized biomarker scores as input to a statistical model
to obtain a first therapy score for the first therapy; providing
the second set of normalized biomarker scores as input to the
statistical model to obtain a second therapy score for the second
therapy; wherein the plurality of therapies comprise at least two
therapies selected from the group consisting of: an anti-PD1
therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha
therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy, and wherein the plurality of
biomarkers associated with each of the plurality of therapies
comprises at least three biomarkers selected from the group of
biomarkers associated with the respective therapy in Table 2.
[0391] In one aspect provided herein is a method, comprising using
at least one computer hardware processor to perform: obtaining
sequencing data about at least one biological sample of a subject;
accessing, in at least one database, biomarker information
indicating a distribution of values for each biomarker, across a
respective group of people, in at least a reference subset of the
plurality of biomarkers, each of the plurality of biomarkers being
associated with at least one therapy in a plurality of therapies;
determining, using the sequencing data and the biomarker
information: a first set of normalized biomarker scores for a first
set of biomarkers associated with a first therapy in the plurality
of therapies; and a second set of normalized biomarker scores for a
second set of biomarkers associated with a second therapy in the
plurality of therapies, wherein the first set of biomarkers is
different from the second set of biomarkers; providing the first
set of normalized biomarker scores as input to a statistical model
to obtain a first therapy score for the first therapy; providing
the second set of normalized biomarker scores as input to the
statistical model to obtain a second therapy score for the second
therapy; wherein the plurality of therapies comprise at least two
therapies selected from the group consisting of: an anti-PD1
therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha
therapy, an anti-cancer vaccine therapy, an anti-angiogenic
therapy, and an anti-CD20 therapy, and wherein the plurality of
biomarkers associated with each of the plurality of therapies
comprises at least three biomarkers selected from the group of
biomarkers associated with the respective therapy in Table 2.
[0392] In some embodiments, the plurality of biomarkers includes a
first biomarker, and wherein determining a normalized score for
each biomarker in at least the subject subset of the plurality of
biomarkers comprises: determining a first normalized score for the
first biomarker using the distribution of values for the first
biomarker. In some embodiments, determining the first normalized
score comprises: determining an un-normalized score for the first
biomarker using the sequencing data; determining a Z-score based on
the first distribution of values for the first biomarker; and
determining a normalized score for the first biomarker based on the
un-normalized score and the Z-score.
[0393] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies as a sum of two
or more scores in the set of normalized biomarker scores for the
subject.
[0394] In some embodiments, determining therapy scores for the
plurality of therapies comprises determining a first therapy score
for a first therapy in the plurality of therapies at least in part
by: determining weights for two or more scores in the set of
normalized biomarker scores for the subject; and determining the
first therapy score as a sum of the two or more scores, summands of
the sum being weighted by the determined weights.
[0395] In some embodiments, determining the weights comprises
determining the weights using a machine learning technique. In some
embodiments, determining the weights comprises determining the
weights using a generalized linear model. In some embodiments,
determining the weights comprises determining the weights using a
logistic regression model.
[0396] In some embodiments, the plurality of therapies comprises a
first therapy and a second therapy different from the first
therapy, and wherein determining therapy scores for the plurality
of therapies comprises: determining a first therapy score for the
first therapy using a first subset of the set of normalized
biomarker scores for the subject; and determining a second therapy
score for the second therapy using a second subset of the set of
normalized biomarker scores for the subject, wherein the second
subset is different from the first subset.
[0397] Some embodiments include recommending at least one of the
plurality of therapies for the subject based on the determined
therapy scores. In some embodiments, recommending the at least one
of the plurality of therapies comprises: ranking the plurality of
therapies based on the determined therapy scores; and recommending
at least a threshold number of top-ranked therapies for the
subject.
[0398] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-PD1 therapy in Table 2.
[0399] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-CTLA4 therapy in Table 2.
[0400] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with IL-2 therapy in Table 2.
[0401] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with IFN alpha therapy in Table 2.
[0402] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-cancer vaccine therapy in Table
2.
[0403] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-angiogenic therapy in Table 2.
[0404] In some embodiments, determining the normalized biomarker
scores for the subject comprises determining a normalized score for
each of at least three biomarkers selected from the group of
biomarkers associated with anti-CD20 therapy in Table 2. In some
embodiments, the anti-CD20 therapy is rituximab.
[0405] Some embodiments include generating a graphical user
interface (GUI) comprising: a first portion associated with a first
therapy in the plurality of therapies, the first portion including
a first plurality of GUI elements, each of the first plurality of
GUI elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a normalized score of the
respective biomarker in the first set of normalized scores; and a
second portion associated with a second therapy in the plurality of
therapies, the second portion including a second plurality of GUI
elements different from the first plurality of GUI elements, each
of the second plurality of GUI elements being associated with a
respective biomarker in the plurality of biomarkers and having at
least one visual characteristic determined based on a normalized
score of the respective biomarker in the second set of normalized
scores; and displaying the generated GUI.
[0406] In some embodiments, the at least one visual characteristic
comprises color of a GUI element and/or size of the GUI element.
Some embodiments include in response to receiving, via the GUI, a
user selection of the first therapy, presenting, via the GUI,
information about at least one biomarker with which at least one of
the first plurality of GUI elements is associated.
[0407] In some embodiments, the first therapy is associated with a
first therapy score and the second therapy is associated with a
second therapy score, and wherein the first portion and the second
portion are positioned, relative to one another in the GUI, based
on relative magnitude of the first therapy score and the second
therapy score.
[0408] In some embodiments, each of the plurality of biomarkers is
selected from the group consisting of: a genetic biomarker, a
cellular biomarker, a saccharide biomarker, a lipid biomarker, a
heterocyclic biomarker, an elementary compound biomarker, an
imaging biomarker, an anthropological biomarker, a personal habit
biomarker, a disease-state biomarker, and an expression
biomarker.
[0409] In some embodiments, the value of one or more genetic
biomarkers is determined through the identification of one or more
mutations, insertions, deletions, rearrangements, fusions, copy
number variations (CNV), or single nucleotide variants (SNV) in the
nucleic acid or protein of the genetic biomarker. In some
embodiments, the one or more genetic biomarkers includes a gene or
marker described in the description and/or the figures. In some
embodiments, one or more genetic biomarkers are selected from the
group consisting of: interferons, cytotoxic proteins, enzymes, cell
adhesion proteins, extracellular matrix proteins and
polysaccharides, cell growth factors, cell differentiation factors,
transcription factors, and intracellular signaling proteins. In
some embodiments, the one or more genetic biomarkers is selected
from the group consisting of: a cytokine, a chemokine, a chemokine
receptor, and an interleukin.
[0410] In some embodiments, the value of one or more cellular
biomarkers is determined through analysis of the number of one or
more types of cells or the percentage of one or more types of cells
within the biological sample. In some embodiments, the one or more
types of cells are selected from the group consisting of malignant
cancerous cells, leukocytes, lymphocytes, stromal cells, vascular
endothelial cells, vascular pericytes, and myeloid-derived
suppressor cells (MDSCs).
[0411] In some embodiments, the value of one or more expression
biomarkers is determined through analysis of the expression level
or enzymatic activity of the nucleic acid or protein of the
expression biomarker.
[0412] In some embodiments, the sequencing data is one or more of:
DNA sequencing data, RNA sequencing data, or proteome sequencing
data. In some embodiments, the sequencing data is obtained using
one or more of the following techniques: whole genome sequencing
(WGS), whole exome sequencing (WES), whole transcriptome
sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray,
DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP)
genotyping.
[0413] In some embodiments, each of the at least one biological
samples is a bodily fluid, a cell sample, a liquid biopsy, or a
tissue biopsy. In some embodiments, the tissue biopsy comprises one
or more samples from one or more tumors or tissues known or
suspected of having cancerous cells.
[0414] In some embodiments, the biomarker information also
comprises results from one or more of the following types of
analyses: blood analysis, cytometry analysis, histological
analysis, immunohistological analysis, and patient history
analysis.
[0415] In some embodiments, each of the therapies are selected from
the group consisting of: surgery, radiation therapy, chemotherapy,
immunotherapy, viral therapy, targeted therapy, hormone therapy,
transplants, phototherapy, cryotherapy, and hyperthermia. In some
embodiments, each of the therapies are selected from immunotherapy
and targeted therapy.
[0416] In some embodiments, the therapy scores are indicative of
response of the subject to administration of one therapy in the
plurality of therapies. In some embodiments, the therapy scores are
indicative of response of the subject to administration of multiple
therapies in the plurality of therapies.
[0417] In one aspect provided herein is a system, comprising: at
least one computer hardware processor; at least one database that
stores biomarker information; and at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by the at least one computer
hardware processor, cause the at least one computer hardware
processor to perform: obtaining sequencing data about at least one
biological sample of a subject; accessing, in the at least one
database, biomarker information indicating a distribution of values
for each biomarker, across a respective group of people, in at
least a reference subset of the plurality of biomarkers, each of
the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
[0418] In one aspect provided herein is at least one non-transitory
computer-readable storage medium storing processor-executable
instructions that, when executed by at least one computer hardware
processor, cause the at least one computer hardware processor to
perform: obtaining sequencing data about at least one biological
sample of a subject; accessing, in at least one database, biomarker
information indicating a distribution of values for each biomarker,
across a respective group of people, in at least a reference subset
of the plurality of biomarkers, each of the plurality of biomarkers
being associated with at least one candidate therapy; determining,
using the sequencing data and the biomarker information, a
normalized score for each biomarker in at least a subject subset of
the plurality of biomarkers to obtain a set of normalized
biomarkers for the subject; identifying the subject as a member of
one or more cohorts based on the set of normalized biomarker scores
for the subject, wherein each of the one or more cohorts is
associated with a positive or negative outcome of the at least one
candidate therapy; and outputting an indication of the one or more
cohorts in which the subject is a member.
[0419] In one aspect a method comprising using at least one
computer hardware processor to perform: obtaining sequencing data
about at least one biological sample of a subject; accessing, in at
least one database, biomarker information indicating a distribution
of values for each biomarker, across a respective group of people,
in at least a reference subset of the plurality of biomarkers, each
of the plurality of biomarkers being associated with at least one
candidate therapy; determining, using the sequencing data and the
biomarker information, a normalized score for each biomarker in at
least a subject subset of the plurality of biomarkers to obtain a
set of normalized biomarkers for the subject; identifying the
subject as a member of one or more cohorts based on the set of
normalized biomarker scores for the subject, wherein each of the
one or more cohorts is associated with a positive or negative
outcome of the at least one candidate therapy; and outputting an
indication of the one or more cohorts in which the subject is a
member.
[0420] In some embodiments, the at least one candidate therapy is
associated with a clinical trial, optionally wherein the clinical
trial is ongoing or the clinical trial is recruiting.
[0421] In some embodiments, the positive outcome is an improvement
in one or more aspects of a cancer or in one or more cancer
symptoms.
[0422] In some embodiments, the improvement in one or more aspects
of a cancer or one or more cancer symptoms is selected from the
group consisting of: decrease in tumor size, decrease in tumor
number, decrease in number or percentage of cancerous cells in the
body of the subject, and slowing of cancer growth.
[0423] In some embodiments, the negative outcome is a cancer
therapy-related adverse effect, an deterioration in one or more
aspects of a cancer, or a deterioration in one or more cancer
symptoms.
[0424] In some embodiments, the cancer therapy-related adverse
effect is selected from: cutaneous toxicity, thrombocytopenia,
hepatotoxicity, neurotoxicity, nephrotoxicity, cardiotoxicity,
hemorrhagic cystitis, immune-related toxicity, and death.
[0425] In some embodiments, the deterioration in one or more
aspects of a cancer or one or more cancer symptoms is selected from
the group consisting of: increase in tumor size, increase in tumor
number, increase in number or percentage of cancerous cells in the
body of the subject, no slowing of cancer growth, and death.
[0426] In some embodiments, the sequencing data is one or more of:
DNA sequencing data, RNA sequencing data, or proteome sequencing
data. In some embodiments, the sequencing data is obtained using
one or more of the following techniques: whole genome sequencing
(WGS), whole exome sequencing (WES), whole transcriptome
sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray,
DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP)
genotyping.
[0427] In some embodiments, the biological sample is from a tumor
or tissue known or suspected of having cancerous cells. In some
embodiments, each of the at least one biological samples is a
bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy.
In some embodiments, the biological sample is blood.
[0428] Some embodiments include generating a graphical user
interface (GUI) comprising: a first portion associated with the at
least one candidate therapy, the first portion including a first
plurality of GUI elements, each of the first plurality of GUI
elements being associated with a respective biomarker in the
plurality of biomarkers and having at least one visual
characteristic determined based on a difference score of the
respective biomarker; and displaying the generated GUI. In some
embodiments, the at least one visual characteristic comprises color
of a GUI element and/or size of the GUI element. Some embodiments
include in response to receiving, via the GUI, a user selection of
the at least one candidate therapy, presenting, via the GUI,
information about at least one biomarker with which at least one of
the first plurality of GUI elements is associated.
EQUIVALENTS AND SCOPE
[0429] The terms "program" or "software" are used herein in a
generic sense to refer to any type of computer code or set of
processor-executable instructions that can be employed to program a
computer or other processor (physical or virtual) to implement
various aspects of embodiments as discussed above. Additionally,
according to one aspect, one or more computer programs that when
executed perform methods of the technology described herein need
not reside on a single computer or processor, but may be
distributed in a modular fashion among different computers or
processors to implement various aspects of the technology described
herein.
[0430] Processor-executable instructions may be in many forms, such
as program modules, executed by one or more computers or other
devices. Generally, program modules include routines, programs,
objects, components, data structures, etc. that perform particular
tasks or implement particular abstract data types. Typically, the
functionality of the program modules may be combined or
distributed.
[0431] Also, data structures may be stored in one or more
non-transitory computer-readable storage media in any suitable
form. For simplicity of illustration, data structures may be shown
to have fields that are related through location in the data
structure. Such relationships may likewise be achieved by assigning
storage for the fields with locations in a non-transitory
computer-readable medium that convey relationship between the
fields. However, any suitable mechanism may be used to establish
relationships among information in fields of a data structure,
including through the use of pointers, tags or other mechanisms
that establish relationships among data elements.
[0432] Various inventive concepts may be embodied as one or more
processes, of which examples have been provided. The acts performed
as part of each process may be ordered in any suitable way. Thus,
embodiments may be constructed in which acts are performed in an
order different than illustrated, which may include performing some
acts simultaneously, even though shown as sequential acts in
illustrative embodiments.
[0433] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, for
example, "at least one of A and B" (or, equivalently, "at least one
of A or B," or, equivalently "at least one of A and/or B") can
refer, in one embodiment, to at least one, optionally including
more than one, A, with no B present (and optionally including
elements other than B); in another embodiment, to at least one,
optionally including more than one, B, with no A present (and
optionally including elements other than A); in yet another
embodiment, to at least one, optionally including more than one, A,
and at least one, optionally including more than one, B (and
optionally including other elements); etc.
[0434] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as an
example, a reference to "A and/or B", when used in conjunction with
open-ended language such as "comprising" can refer, in one
embodiment, to A only (optionally including elements other than B);
in another embodiment, to B only (optionally including elements
other than A); in yet another embodiment, to both A and B
(optionally including other elements); etc.
[0435] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The disclosure includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The disclosure includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0436] Furthermore, the described methods and systems encompass all
variations, combinations, and permutations in which one or more
limitations, elements, clauses, and descriptive terms from one or
more of the listed claims is introduced into another claim. For
example, any claim that is dependent on another claim can be
modified to include one or more limitations found in any other
claim that is dependent on the same base claim. Where elements are
presented as lists, e.g., in Markush group format, each subgroup of
the elements is also disclosed, and any element(s) can be removed
from the group. It should it be understood that, in general, where
the systems and methods described herein (or aspects thereof) are
referred to as comprising particular elements and/or features,
certain embodiments of the systems and methods or aspects of the
same consist, or consist essentially of, such elements and/or
features. For purposes of simplicity, those embodiments have not
been specifically set forth in haec verba herein.
[0437] It is also noted that the terms "including," "comprising,"
"having," "containing", "involving", are intended to be open and
permits the inclusion of additional elements or steps. Where ranges
are given, endpoints are included. Furthermore, unless otherwise
indicated or otherwise evident from the context and understanding
of one of ordinary skill in the art, values that are expressed as
ranges can assume any specific value or sub-range within the stated
ranges in different embodiments of the described systems and
methods, to the tenth of the unit of the lower limit of the range,
unless the context clearly dictates otherwise.
[0438] Use of ordinal terms such as "first," "second," "third,"
etc., in the claims to modify a claim element does not by itself
connote any priority, precedence, or order of one claim element
over another or the temporal order in which acts of a method are
performed. Such terms are used merely as labels to distinguish one
claim element having a certain name from another element having a
same name (but for use of the ordinal term).
[0439] Additionally, as used herein the terms "patient" and
"subject" may be used interchangeably. Such terms may include, but
are not limited to, human subjects or patients. Such terms may also
include non-human primates or other animals.
[0440] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present disclosure that fall within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the systems and methods described herein can be
excluded from any claim, for any reason, whether or not related to
the existence of prior art.
[0441] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
disclosure, as defined in the following claims.
* * * * *