U.S. patent application number 17/502922 was filed with the patent office on 2022-02-10 for increasing responses to checkpoint inhibitors by extracorporeal apheresis.
This patent application is currently assigned to IMMUNICOM, INC.. The applicant listed for this patent is IMMUNICOM, INC.. Invention is credited to Thomas Emanuel ICHIM, Amir JAFRI, Steven Francis JOSEPHS, Stephen Michael PRINCE, David L. SCHLOTTERBECK, Robert SEGAL.
Application Number | 20220041731 17/502922 |
Document ID | / |
Family ID | 1000005902563 |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220041731 |
Kind Code |
A1 |
ICHIM; Thomas Emanuel ; et
al. |
February 10, 2022 |
INCREASING RESPONSES TO CHECKPOINT INHIBITORS BY EXTRACORPOREAL
APHERESIS
Abstract
The invention provides means, methods, and compositions of
matter useful for enhancing tumor response to checkpoint
inhibitors. In one embodiment, the invention teaches utilization of
extracorporeal apheresis, specifically removal of various tumor
derived, or tumor microenvironment derived immunological "blocking
factors". In one embodiment the invention provides the removal of
soluble TNF-alpha receptors (sTNF-Rs) as a means of augmenting
efficacy of immune checkpoint inhibitors. In one specific
embodiment removal of sTNF-Rs is utilized to enhance efficacy of
inhibitors of the PD-1/PD-L1 pathway, and/or the CD28/CTLA-4
pathway.
Inventors: |
ICHIM; Thomas Emanuel; (San
Diego, CA) ; JOSEPHS; Steven Francis; (San Diego,
CA) ; PRINCE; Stephen Michael; (San Diego, CA)
; JAFRI; Amir; (San Diego, CA) ; SEGAL;
Robert; (San Diego, CA) ; SCHLOTTERBECK; David
L.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IMMUNICOM, INC. |
SAN DIEGO |
CA |
US |
|
|
Assignee: |
IMMUNICOM, INC.
SAN DIEGO
CA
|
Family ID: |
1000005902563 |
Appl. No.: |
17/502922 |
Filed: |
October 15, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17175503 |
Feb 12, 2021 |
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17502922 |
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PCT/US2019/031184 |
May 7, 2019 |
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17175503 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/2818 20130101;
C07K 2317/24 20130101; C07K 16/2827 20130101; C07K 2317/76
20130101; A61M 2202/0415 20130101; A61M 1/3693 20130101; A61M
1/3496 20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28; A61M 1/34 20060101 A61M001/34; A61M 1/36 20060101
A61M001/36 |
Claims
1-18. (canceled)
19. A method of enhancing an efficacy of an antibody administered
to a patient, comprising the steps of: (a) administering an
antibody capable of suppressing activity of a checkpoint protein
selected from a group consisting of a LAG3, a Tim3, a 2B4, a A2aR,
a ID02, a BTLA, a DR3, a GAL9, a HVEM, a ID01, a KIR, a LAIR, a
LIGHT, a MARCO, a PS, a SLAM, a TIGIT, a VISTA, a VTCN1, a CD2, a
CD20, a CD30, a CD33, a CD52, a CD70, a CD112, a CD160, and a CD226
molecule; (b) extracorporeally removing an immunological blocking
factor that inhibits the effectiveness of the antibody from blood
or a blood component of the patient.
20. The method of claim 19, wherein the antibody is selected from a
group consisting of IMP321, ibritumomab tiuxetan, ofatumumab,
rituximab, obinutuzumab, tositumomab, brentuximab vedotin,
gemtuzumab ozogamicin, and alemtuzumab.
21. The method of claim 19, wherein the immunological blocking
factor is a soluble tumor necrosis factor (TNF)-alpha receptor.
22. The method of claim 21, wherein step (b) is performed using an
affinity capture substrate that comprises an immobilized TNF-alpha
molecule comprising one or more of a native TNF-alpha molecule and
a mutated TNF-alpha molecule.
23. The method of claim 22, wherein the immobilized TNF-alpha
molecule is a trimer.
24. The method of claim 19, further comprising after step (b)
administering an antibody capable of suppressing activity of a
checkpoint protein selected from a group consisting of a LAG3, a
Tim3, a 2B4, a A2aR, a ID02, a BTLA, a DR3, a GAL9, a HVEM, a ID01,
a KIR, a LAIR, a LIGHT, a MARCO, a PS, a SLAM, a TIGIT, a VISTA, a
VTCN1, a CD2, a CD20, a CD30, a CD33, a CD52, a CD70, a CD112, a
CD160, and a CD226 molecule one or more additional times to the
patient.
25. The method of claim 19, further comprising after step (b)
extracorporeally removing one or more additional times an
immunological blocking factor that inhibits the effectiveness of
the antibody from blood or a blood component of the patient.
26. The method of claim 19, wherein step (a) is performed before
step (b).
27. The method of claim 19, wherein step (b) is performed before
step (a).
28. An extracorporeal system for enhancing an efficacy of an
antibody administered to a patient, comprising: a column configured
to deplete a portion of an immunological blocking factor that
reduces the efficacy of the antibody from blood or a blood
component of the patient; wherein the antibody is capable of
suppressing activity of a checkpoint protein selected from the
group consisting of a LAG3, a Tim3, a 2B4, a A2aR, a ID02, a BTLA,
a DR3, a GAL9, a HVEM, a ID01, a KIR, a LAIR, a LIGHT, a MARCO, a
PS, a SLAM, a TIGIT, a VISTA, a VTCN1, a CD2, a CD20, a CD30, a
CD33, a CD52, a CD70, a CD112, a CD160, and a CD226 molecule.
29. The system of claim 28, wherein the antibody is selected from a
group consisting of IMP321, ibritumomab tiuxetan, ofatumumab,
rituximab, obinutuzumab, tositumomab, brentuximab vedotin,
gemtuzumab ozogamicin, and alemtuzumab.
30. The system of claim 28, wherein the immunological blocking
factor is a soluble tumor necrosis factor (TNF)-alpha receptor.
31. The system of claim 30, wherein the column comprises an
affinity capture substrate that comprises an immobilized TNF-alpha
molecule comprising one or more of a native TNF-alpha molecule and
a mutated TNF-alpha molecule.
32. The system of claim 31, wherein the affinity capture substrate
is a trimer.
Description
BACKGROUND
[0001] There is an increasing prevalence of cancer in human and its
significant contribution to mortality means there is a continuing
need for new therapies. Elimination of the cancer, a reduction in
its size, the disruption of its supporting vasculature, or reducing
the number of cancer cells circulating in the blood or lymph
systems are goals of current cancer therapies. Mechanistically,
therapies for cancer are designed to combat tumors or cells
metastasizing from tumors typically rely on a cytotoxic activity.
That activity might be a cytotoxic effect an active agent has
itself or it might be an effect employed indirectly by the active
agent such as through the modulation of immune responses.
[0002] It is known that genetic and epigenetic changes occur in
tissues as they transform to take on the phenotype of a cancer
cell. Different steps in the malignant transformation process,
including acquisition of the mutator phenotype, which is associated
with loss of tumor suppressor activity, often results in the
generation of neoantigens, which are subject to immune
recognition.
[0003] Various attempts have been made to help the immune system to
fight tumors. One early approach involved a general stimulation of
the immune system through the administration of bacteria (live or
killed) to elicit a general immune response which would also be
directed against the tumor. Existing innate stimulators of immunity
include BCG [1-10], lyophilized incubation mixture of group A
Streptococcus pyogenes (OK-432) [11-26], CSF-470 [27, 28], as well
as doses of chemotherapies that can selectively suppress Treg cells
[29-39].
[0004] As far back as 1975 [40], it was known that administration
of non-specific immune activators could induce local and in some
cases systemic regression of cancer. For example, in one study, 6
patients with intradermal metastases of malignant melanoma were
treated with intralesional BCG. Four patients showed a good
response with regression of injected, and in some cases, uninjected
lesions, whereas the other two developed metastatic visceral
disease and died. Three of the six patients had complete regression
of all lesions, and one exhibited complete regression of untreated
lesions. All remain free of disease. The fourth patient had
complete regression of injected and of some untreated lesions, but
developed widespread dissemination and died. Three of four
responders (i.e. those patients in whom treated lesions decreased
in size by more than 50% for more than 1 month) showed a dramatic
increase in lymphocyte stimulation to melanoma antigens. All
responders (four out of four) had a marked increase to
phytohemagglutinin (PHA), whereas non responders had no increase in
lymphocyte stimulation either to melanoma antigens or PHA. These
data suggested the other important point, which is that innate
immune activation can lead to stimulation of antigen-specific T
cell and B cell mediated immune responses. Recent approaches aimed
at helping the immune system specifically to recognize
tumor-specific antigens involve immunization with cancer-specific
antigens, typically combined with an adjuvant (a substance which is
known to cause or enhance an immune response) to the subject. Tumor
specific antigens are well known and include the group of cancer
testes antigens (CT antigens) or germ cell antigens that are
reactivated in cancerous tissues. It is known that the usual lack
of a powerful immune response to tumor associated antigens (TAAs)
is due to a combination of factors. T cells have a key role in the
immune response, which is mediated through antigen recognition by
the T cell receptor (TCR), and they coordinate a balance between
co-stimulatory and inhibitory signals known as immune checkpoints.
These inhibitory signals function as natural suppressors of the
immune system as an important mechanism for for maintenance of
self-tolerance and to protect tissues from damage when the immune
system is responding to pathogenic infection. However, disregulated
immune suppression reduces what could otherwise be a helpful
response by the body to avoid the development of tumors. Cytokines,
other stimulatory molecules such as CpG (stimulating dendritic
cells), Toll-like receptor ligands and other molecular adjuvants
enhance the immune response. Co-stimulatory interactions involving
T cells directly can be enhanced using agonistic antibodies to
receptors including OX40, CD28, CD27 and CD137. Other immune system
activating therapies include blocking and/or depleting inhibitory
cells or molecules and include the use of antagonistic antibodies
against what are known as immune checkpoints [41]. It is known that
immune cells express proteins that are immune checkpoints that
control and down-regulate the immune response. These are best
defined in T lymphocytes and include PD-1, CTLA-4, TIM-3 and LAG3.
Tumor cells express the ligands to these receptors. When T cells
bind the ligand to these proteins on the tumor cells, the T cell is
turned off and does not attempt to attack the tumor cell. Thus,
checkpoint immune suppression is part of the complex strategy used
by the tumor to evade the patient's immune system and is
responsible for resistance to immunotherapy. Biopharmaceutical
companies have successfully developed therapeutic checkpoint
inhibitors that block the receptor/ligand interaction to promote
the adaptive immune response to the tumor. Six checkpoint
inhibitors are currently approved, pembrolizumab, nivolumab,
atezolizumab, avelumab, durvalumab, and ipilimumab for a wide
variety of solid tumors including melanoma, lung, bladder, gastric
cancers and others. T cells are central to the immune response to
cancers and there is interest in the field in using tumor
infiltrating lymphocytes (TILs) in the treatment and understanding
of cancer. Through their T cell receptors (TCRs), T cells are
reactive to specific antigens within a tumor. Tumor cells carry
genetic mutations, many of which contribute directly or indirectly
to malignancy. A mutation in an expressed sequence will typically
result in a neoantigen, an antigen that is not known to the immune
system and thus recognized as foreign and able to elicit an immune
response. The importance of TIL is that they are associated with
superior patient prognosis including in gastric cancer [42], breast
cancer [43-46], melanoma [47], head and neck cancer [48], thus
suggesting an active role of the immune system in contributing to
cancer survival.
[0005] Unfortunately, despite the great advances in understanding
of the immune-cancer interaction, and development of novel first in
class drugs around this concept, many patients still do not respond
to immunotherapies, and in some cases, those that respond suffer
from relapse. The current invention teaches means of augmenting
efficacy of immunotherapies specifically of checkpoint inhibitors,
by removal of tumor derived and/or tumor microenvironment derived
immunological blocking factors using extracorporeal means.
SUMMARY
[0006] Embodiments herein are directed to methods of enhancing the
efficacy of an immune checkpoint inhibitor administered to a
patient suffering from a tumor comprising: identifying a patient
suffering from a tumor; administering an immunological checkpoint
inhibitor to said patient to treat said tumor or ameliorate the
effects of said tumor; extracorporeally removing immunological
blocking factors that inhibit the effectiveness of said
immunological checkpoint inhibitor in an amount sufficient to
augment the efficacy of said immunological checkpoint inhibitor in
either treating or ameliorating the effects of said tumor, wherein
said extracorporeal removal is conducted at a time selected from
the group consisting of: before, concurrently, and subsequent to
the administration of said immunological checkpoint inhibitor.
[0007] More specifically, disclosed herein are methods wherein said
efficacy of said checkpoint inhibitor is based on an endpoint
selected from the group consisting of: a) tumor regression; b)
tumor stabilization; c) reduction in tumor growth; d) inhibition of
metastasis; e) stabilization of metastasis; f) reduction of
metastatic growth; g) encapsulation of tumor and/or metastasis; h)
augmentation of cytokines associated with tumor inhibition; i)
decrease in cytokines associated with tumor progression; j)
suppression of angiogenesis; k) augmentation of tumor infiltrating
lymphocytes; l) switch of intratumoral macrophages from M2 to M1
phenotype; m) augmentation of tumor infiltrating dendritic cells;
n) augmentation of tumor infiltrating killer T-cells o) reduction
of tumor associated T regulatory cells; and p) reduction in tumor
associated myeloid suppressor cells.
[0008] According to further embodiments, said checkpoint inhibitor
is an agent capable of suppressing activity of a molecule selected
from the group consisting of: PD-1, PD-L1, CTLA-4, PD-L2, LAG3,
Tim3, 2B4, A2aR, ID02, B7413, B7-H4, BTLA, CD2, CD20, CD27, CD28,
CD30, CD33, CD40, CD52, CD70, CD112, CD137, CD160, CD226, CD276,
DR3, OX-40, GAL9, GITR, ICOS, HVEM, IDO1, KIR, LAIR, LIGHT, MARCO,
PS, SLAM, TIGIT, VISTA, and VTCN1
[0009] According to other embodiments said immunological blocking
factor is soluble TNF-alpha receptor.
[0010] According to further embodiments, disclosed herein are
methods wherein said immunological blocking factor is selected from
the group consisting of: a) soluble HLA-G; b) soluble MICA; c)
interleukin-10; d) interleukin-20; e) VEGF; f) soluble IL-2
receptor; g) soluble IL-15 receptor; h) interleukin-35 and i)
soluble interferon gamma receptor.
[0011] According to more specific embodiments, said removal of
soluble TNF-alpha receptor is performed by affinity capture to
TNF-alpha trimers.
[0012] According to further embodiments said checkpoint inhibitor
is administered via a route selected from the group consisting of:
intravenously, intramuscularly, parenterally, nasally,
intratumorally, intraosseously, subcutaneously, sublingually,
intrarectally, intrathecally, intraventricularly, orally,
intraocularly, topically, or via inhalation, nanocell and/or
nanobubble injection.
[0013] According to more specific embodiments, the immunological
checkpoint inhibitor is selected from the group consisting of PD-1,
PD-L1, and CTLA-4.
[0014] According to other embodiments, the inhibitor of PD-1 is an
anti-PD-1 antibody selected from the group consisting of nivolumab
and pembrolizumab.
[0015] Further embodiment are directed to methods wherein the
inhibitor of PD-L1 is anti-PD-L1 antibody selected from the group
consisting of: BMS-936559, durvalumab, atezolizumab, avelumab,
MPDL3280A, MED14736, MSB0010718C, and MDX1105-01.
[0016] According to other embodiments, the inhibitor of CTLA-4 is
an anti-CTLA-4 antibody selected from the group consisting of
ipilimumab and tremelimumab.
[0017] According to certain embodiments, said removal of said
soluble TNF-alpha receptor is performed using an extracorporeal
affinity capture substrate comprising immobilized TNF-alpha
molecules selected from the group consisting of: TNF-alpha trimers,
native TNF-alpha molecules, and mutated forms of TNF-alpha, wherein
said immobilized TNF-alpha molecules on the extracorporeal affinity
capture substrate have at least one binding site capable of
selectively binding to soluble TNF alpha receptor from a biological
fluid.
[0018] Further methods include embodiments wherein said removal of
immunological blocking factors is performed using an apheresis
system utilizing centrifugal plasma separation.
[0019] Additional methods include embodiments, wherein said removal
of immunological blocking factors is performed using an apheresis
system utilizing membrane plasma separation.
[0020] Other aspects embody methods wherein enhancing efficacy of
an immune checkpoint inhibitor is accomplished by performing one or
more clinical procedures involving the removal of tumor derived
blocking factors to prepare and/or condition the patient.
[0021] Still further embodiments include methods wherein said
removal of soluble TNF-alpha receptor is performed by affinity
capture to TNF-alpha trimers.
[0022] According to more specific embodiments said checkpoint
inhibitor is administered intravenously, intramuscularly,
parenterally, nasally, intratumorally, intraosseously,
subcutaneously, sublingually, intrarectally, intrathecally,
intraventricularly, orally, topically, or via inhalation, nanocell
and/or nanobubble injection.
[0023] According to further embodiments said extracorporeal removal
of immune blocking factors primes antigen presenting cells for
enhanced ability to produce interleukin-12 subsequent to
administration of a checkpoint inhibitor.
[0024] Further embodiments are directed to an immune checkpoint
inhibitor for use in a method of treating a tumor in a patient, the
method comprising: identifying a patient suffering from a tumor;
administering an immunological checkpoint inhibitor to said patient
to treat said tumor or ameliorate the effects of said tumor; and
extracorporeally removing immunological blocking factors that
inhibit the effectiveness of said immunological checkpoint
inhibitor, wherein said extracorporeal removal is conducted at a
time selected from the group consisting of: before, concurrently,
and subsequent to the administration of said immunological
checkpoint inhibitor. All methods disclosed herein can be used with
said immune checkpoint inhibitors.
DESCRIPTION OF THE INVENTION
[0025] The invention discloses means of augmenting therapeutic
ability of immunological checkpoint inhibitors by removal of
immunological blocking factors through extracorporeal means. In one
embodiment, the invention relates to the field of cancer therapy,
specifically means of augmenting efficacy of cancer therapy. In
particular, the invention provides methods of generating T cell
populations capable of promoting the suppression of cancer, as well
as directly killing the cancer. As used herein, the term
"treatment" refers to clinical intervention in an attempt to alter
the natural course of the individual or cell being treated, and may
be performed either for prophylaxis or during the course of
clinical pathology. Desirable effects include preventing occurrence
or recurrence of disease, alleviation of symptoms, and.
diminishment of any direct or indirect pathological consequences of
the disease, preventing metastasis, lowering the rate of disease
progression, amelioration or palliation of the disease state, and
inducing remission or improving prognosis.
[0026] The term "extracorporeal means" is defined as the use of an
extracorporeal device or system through which blood or blood
constituents obtained from a patient are passed through a device
for the removal of the immune inhibitor(s) and wherein the blood or
blood constituents that are depleted of immune inhibitor(s) are
reinfused into the patient. The extracorporeal device is comprised
of materials that selectively binds to and captures the specified
inhibitor(s) to prevent them from being reinfused into the
patient.
[0027] The term "affinity capture" means the selective binding of a
specific substance or molecule by a chemical attraction.
[0028] The term "affinity capture substrate" means a material
comprising an affinity capture molecule.
[0029] The term "antibody" includes therapeutic antibodies suitable
for treating patients; such as abagovomab, adecatumumab,
afutuzumab, alemtuzumab, altrimomab, amatuximab, anatumomab,
arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab,
blinatumomab, brentuximab, cantuzumab, calumaxontab, cetuximab,
citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab,
drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab,
dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab,
etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab,
futuximab, ganitumab, gemluzumab, girentuximab, glembatumumab,
ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab,
intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab,
lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab,
milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab,
naptumomab, necitumumab, nimotuzumab, nofetumomabn, ocaratuzumab,
ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab,
panitumumab, parsatuzumab, patritumab, perntumomab, pertuzumab,
pintumomab, pritumumab, racotumomab, radretumab, rilotumumab,
rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab,
sirntuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab,
teprotumumab, tigatuzumab, tocilizumab, tositumomab, trastuzumab,
tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab,
zalutumumab, CC49 and 3F8. In some embodiments the invention
teaches the combination use of extracorporeal removal of blocking
factors as a means of augmenting therapeutic efficacy of the
mentioned antibodies. In other embodiments the combination of
antibodies, together with extracorporeal removal of blocking
factors, is further combined with administration of checkpoint
inhibitors. The invention is particularly of importance to
therapeutic antibodies whose actions are mediated by antibody
dependent cellular toxicity. The mentioned antibodies can be
utilized individually or in combination. Furthermore administration
of other immune modulators is envisioned within the scope of the
invention. Immune modulators may be activators of innate immunity
such as toll like receptor agonists. Other immune modulators
stimulate adaptive immunity such as T and B cells. Furthermore,
immune stimulation by be achieved by removal of immune suppressive
cells utilizing approaches that deplete myeloid derived suppressor
cells, Th3 cells, T regulatory cells, type 2 neutrophils, type 2
macrophages and eosinophils.
[0030] The terms "antigen-presenting cell (s)", "APC" or "APCs"
include both intact, whole cells as well as other molecules (all of
allogeneic origin) which are capable of inducing the presentation
of one or more antigens, preferably in association with class I MHC
molecules, and all types of mononuclear cells which are capable of
inducing an allogeneic immune response. Preferably whole viable
cells are used as APCs. Examples of suitable APCs are, but not
limited to, whole cells such as monocytes, macrophages, DCs,
monocyte-derived DCs, macrophage-derived DCs. B cells and myeloid
leukemia cells e. g. cell lines THP-1, U937, HL-60 or CEM-CM3.
Myeloid leukemia cells are said to provide so called pre-monocytes.
In some embodiments of the invention, tumor induced immaturity of
antigen presenting cells is overcome by extracorporeal removal of
tumor associated blocking factors. Said removal results in a
predisposition of antigen presenting cells to mature in response to
administration of checkpoint inhibitors.
[0031] The terms "cancer", "neoplasm" and "tumor" are used
interchangeably and in either the singular or plural form, as
appearing in the present specification and claims, refer to cells
that have undergone a malignant transformation that makes diem
pathological to the host organism. Primary cancer cells (that is,
cells obtained from near the site of malignant transformation) can
he readily distinguished from non-cancerous cells by
well-established techniques, particularly histological examination.
The definition of a cancer cell, as used herein, includes not only
a primary cancer cell, but also any cell derived from a cancer cell
ancestor. This includes metastasized cancer cells, and in vitro
cultures and cell lines derived from cancer cells. When referring
to a type of cancer that normally manifests as a solid tumor, a
"clinically detectable" tumor is one that is detectable on the
basis of tumor mass; e. g. by such procedures as CAT scan, magnetic
resonance imaging (MRI), X-ray, ultrasound or palpation.
Non-limiting examples of tumors/cancers relevant for the present
invention are carcinomas (e.g. breast cancer, prostate cancer, lung
cancer, colorectal cancer, renal cancer, gastric cancer and
pancreatic cancer), sarcomas (e.g. bone cancer and synovial
cancer), neuro-endocrine tumors (e.g. glioblastoma, medulloblastoma
and neuroblastoma), leukemias, lymphomas and squamous cell cancer
(e.g. cervical cancer, vaginal cancer and oral cancer). Further,
non-limiting examples of tumors/cancers relevant for the present
invention are, glioma, fibroblastoma, neurosarcoma, uterine cancer,
melanoma, testicular tumors, astrocytoma, ectopic hormone-producing
tumor, ovarian cancer, bladder cancer, Wilm's tumor, vasoactive
intestinal peptide secreting tumors, head and neck squamous cell
cancer, esophageal cancer, or metastatic cancer. Prostate cancer
and breast cancer are particularly preferred.
[0032] For the practice of the invention, the term "chemotherapy"
is meant to encompass any non-proteinaceous (i.e, non-peptidic)
chemical compound useful in the treatment of cancer. Examples of
chemotherapeutic agents include reactive oxygen agents such as
artimesinin and alkylating agents such as thiotepa and
cyclophosphamide (CYTOXAN.RTM.); alkyl sulfonates such as busulfan,
improsulfan and piposulfan; aziridines such as benzodopa,
carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including alfretamine, triemylenemelamine,
triethylenephosphoramide, triethylenethiophosphoramide and
trimemylolomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including synthetic analogue
topotecan); bryostatin; cailystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogues);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
dolastatin; duocarmycin (including the synthetic analogues, KW-2189
and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, cyclophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosoureas such as carmustine, chlorozotocin,
foremustine, lomustine, nimustine, ranimustine; antibiotics such as
the enediyne antibiotics (e.g., calichemicin, especially
calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew,
Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin;
as well as neocarzinostatin chromophore and related chromoprotein
enediyne antibiotic chromomophores), aclacinomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin,
carminomycin, carzinophilin, chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin
(Adramycin.TM.) (including morpholine-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin and
deoxydoxorubicin), epirubicin, esorubicin, idarubicin,
marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, zorubicin; anti-metabolites such as
methotrexate and 5-fluorouracil (5-FU); folic acid analogues such
as demopterin, methotrexate, pteropterin, trimetrexate; purine
analogs such as fludarabine, 6-mercaptopurine, thiamiprine,
thioguanine; pyrimidine analogues such as ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine; androgens such as calusterone,
dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replinisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformthine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; leucovorin; lonidamine; maytansinoids such as maytansine
and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine;
pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine;
folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;
PSK; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-trichlorotriemylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethane; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL.RTM.,
Bristol Meyers Squibb Oncology, Princeton, N.J.) and docetaxel
(TAXOTERE.RTM., Rhone-Poulenc Rorer, Antony, France); chlorambucil;
gemcitabine (GEMZAR.RTM.); 6-thioguanine; mercaptopurine;
methotrexate; platinum analogs such as cisplatin and carboplatin;
vinblastine; platinum; etoposide (VP-16); ifosfamide;
mitroxantrone; vincristine; vinorelbine (NAVELBINE.RTM.);
novantrone; teniposide; edatrexate; daunomycin; aminopterin;
xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylomithine (DMFO); retinoids such as retinoic acid;
capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan)
and pharmaceutically acceptable salts, acids or derivatives of any
of the above. In some embodiments the efficacy of chemotherapy is
augmented by utilization of extracorporeal removal of blocking
factors. Furthermore, combination of the mentioned chemotherapies
may be utilized together with checkpoint inhibitors. The invention
is particularly relevant in situations where efficacy of
chemotherapy is related to immunological activity.
[0033] The terms "extracorporeal system" and "extracorporeal
removal" refer to one or methods for depleting concentrations of
substances from whole blood and/or plasma, wherein said substances
are immune suppressive. Methods for depleting substances from
plasma can utilize systems that perform plasma separation using
centrifugal force or separation via membrane, including but not
limited to tangential flow systems and/or capillary means. in one
embodiment, said extracorporeal means is a single-chain TNF-alpha
based affinity column, termed the "LSV-02" device, which may be
used in combination with the Terumo Optia apheresis system.
[0034] The term "myeloid suppressor cell" is equivalent to immature
myeloid progenitor cells, myeloid derived suppressor cells, natural
suppressor cells, or immature neutrophil/monocyte precursors.
[0035] The terms "vaccine", "immunogen", or immunogenic
composition" are used herein to refer to a compound or composition
that is capable of conferring a degree of specific immunity when
administered to a human or animal subject. As used in this
disclosure, a "cellular vaccine" or "cellular immunogen" refers to
a composition comprising at least one cell population, which is
optionally inactivated, as an active ingredient. The immunogens,
and immunogenic compositions of this invention are active, which
mean that they are capable of stimulating a specific immunological
response (such as an anti-tumor antigen or anti-cancer cell
response) mediated at least in part by the immune system of the
host. The immunological response may comprise antibodies,
immunoreactive cells (such as helper/inducer or cytotoxic cells),
or any combination thereof, and is preferably directed towards an
antigen that is present on a tumor towards which the treatment is
directed. The response may be elicited or re-stimulated in a
subject by administration of either single or multiple doses. A
compound or composition is "immunogenic" if it is capable of
either: a) generating an immune response against an antigen (such
as a tumor antigen) in a naive individual; or b) reconstituting,
boosting, or maintaining an immune response in an individual beyond
what would occur if the compound or composition was not
administered. A composition is immunogenic if it is capable of
attaining either of these criteria when administered in single or
multiple doses.
[0036] The term "T-cell response" means the specific proliferation
and activation of effector functions induced by a peptide in vitro
or in vivo. For MHC class 1 restricted cytotoxic T cells, effector
functions may be lysis of peptide-pulsed, peptide-precursor pulsed
or naturally peptide-presenting target cells, secretion of
cytokines, preferably Interferon-gama, TNF-alpha, or IL-2 induced
by peptide, secretion of effector molecules, preferably granzymes
or perforins induced by peptide, or degranulation.
[0037] The term "peptide" is used herein to designate a series of
amino acid residues, connected one to the other typically by
peptide bonds between the alpha-amino and carbonyl groups of the
adjacent amino acids. The peptides are preferably 9 amino acids in
length, but can be as short as 8 amino acids in length, and as long
as 10, 11, 12 amino acids or even longer, and in case of MHC class
II peptides (e.g. elongated variants of the peptides of the
invention) they can be as long as 15, 16, 17, 18, 19, 20 or 23 or
more amino acids in length. Furthermore, the term "peptide" shall
include salts of a series of amino acid residues, connected one to
the other typically by peptide bonds between the alpha-amino and
carbonyl groups of the adjacent amino acids. Preferably, the salts
are pharmaceutical acceptable salts of the peptides, such as, for
example, the chloride or acetate (trifluoro-acetate) salts. It has
to be noted that the salts of the peptides according to the present
invention differ substantially from the peptides in their state(s)
in vivo, as the peptides are not salts in vivo. The term "peptide"
shall also include "oligopeptide". The term "oligopeptide" is used
herein to designate a series of amino acid residues, connected one
to the other typically by peptide bonds between the alpha-amino and
carbonyl groups of the adjacent amino acids. The length of the
oligopeptide is not critical to the invention, as long as the
correct epitope or epitopes are maintained therein. The
oligopeptides are typically less than about 30 amino acid residues
in length, and greater than about 15 amino acids in length.
[0038] The human in need thereof may be an individual who has or is
suspected of having a cancer. In some of variations, the human is
at risk of developing a cancer (e.g., a human who is genetically or
otherwise predisposed to developing a cancer) and who has or has
not been diagnosed with the cancer. As used herein, an "at risk"
subject is a subject who is at risk of developing cancer (e.g., a
hematologic malignancy). The subject may or may not have detectable
disease, and may or may not have displayed detectable disease prior
to the treatment methods described herein. An at-risk subject may
have one or more so-called risk factors, which are measurable
parameters that correlate with development of cancer, such as
described herein. A subject having one or more of these risk
factors has a higher probability of developing cancer than an
individual without these risk factor(s). These risk factors may
include, for example, age, sex, race, diet, history of previous
disease, presence of precursor disease, genetic (e.g., hereditary)
considerations, and environmental exposure. In some embodiments, a
human at risk for cancer includes, for example, a human whose
relatives have experienced this disease, and those whose risk is
determined by analysis of genetic or biochemical markers. Prior
history of having cancer may also be a risk factor for instances of
cancer recurrence. In some embodiments, provided herein is a method
for treating a human who exhibits one or more symptoms associated
with cancer (e.g., a hematologic malignancy). In some embodiments,
the human is at an early stage of cancer. In other embodiments, the
human is at an advanced stage of cancer.
[0039] Overall survival (OS) is defined as the time elapsed from
start of treatment until death of any cause. Progression Free
Survival (PFS) (RECIST 1.1) is calculated from start of treatment
until disease progression or death. Objective response rate [CR
(Complete Response) or PR (Partial Response) or SD (Stable
Disease)] is defined as the percent of patients with best confirmed
response CR or PR or SD, using CT or MRI, and determined by a
central reader per RECIST 1.1, The response must be confirmed by a
subsequent determination greater than or equal to 4 weeks apart, In
some instances PET is used. The evaluations and measurements are
performed at screening, then at 8-week intervals starting from
first treatment until PD (Progressive Disease) or initiation of
another or additional anti-tumor therapy, whichever occurs first.
In addition, scans are performed at each long-term follow-up visit
until progression.
[0040] In one embodiment of the invention patients are chosen in
which a high degree of cancer associated immune suppression
present. Immune suppression is assessed using different means known
in the art and can include quantification of number of immune cells
in circulation, quantification of activity of immune cells in
circulation, quantification of the number of immune cells found
intratumorally, quantification of activity of immune cells found
intratumorally, quantification of the number of immune cells found
peritumorally, and quantification of activity of immune cells found
peritumorally. In some embodiments of the invention, quantification
of immune cells comprises identification and assessment of activity
of cells possessing tumor cytolytic and/or tumor inhibitory
activity, such cells include natural killer cells (NK), gamma delta
T cells, natural killer T cells (NKT), innate lymphoid cells,
cytotoxic T lymphocytes (CTL), and helper T cells (Th). Activities
of immune cells could be ability to stimulate other immune cells,
killing activity, tumor-growth inhibitory activity, as well as
suppression of angiogenesis. Other means of assessing suppression
of immunity includes quantification of immune suppressive cells.
For example, elevations in immature dendritic cells, Th2 cells, Th3
cells, myeloid suppressor cells, M2 macrophages, T regulatory
cells, N2 neutrophils, and infiltration by mesenchymal stem cells
possessing immune suppressive properties, are all measurements for
selecting patients with immune suppression.
[0041] In some embodiments, extracorporeal removal of blocking
factors is utilized to reduce the immune modulatory activity of
myeloid suppressor cells as a means of inducing immunological
activation. Myeloid suppressor cells are believed to be similar to
the "natural suppressor" cells described by the Singhal group in
the 1970s. Natural suppressor cells were found to be bone marrow
derived cells possessing ability to antigen-nonspecifically
suppress T cell proliferation after immune activation [49-55], and
are upregulated by cancer and pregnancy [56-63]. These properties
are similar to the currently described properties of myeloid
derived suppressor cells [64].
[0042] In some embodiments of the invention, vitamin D3 is added to
extracorporeal removal of blocking factors in order to augment
differentiation and/or loss of immune suppressive ability of said
myeloid derived suppressor cells. Utilization of vitamin D3 to
reduce cancer associated immune suppression is described in this
publication and incorporated by reference [65, 66].
[0043] The invention teaches that in patients with pre-existing
immune suppression, removal of extracorporeal blocking factors may
be used to increase efficacy of checkpoint inhibitor drugs. For the
practice of the invention, various checkpoint inhibitors may be
utilized together with extracorporeal removal of immunological
blocking factors for enhanced therapeutic activity. Examples of
such checkpoint inhibitors include: a) Inhibitors of Programmed
Death 1 (PD-1, CD279), such as nivolumab (OPDIVOR.TM., BMS-936558,
MDX1106, or MK-34775), and pembrolizumab (KEYTRUDA.RTM., MK-3475,
SCH-900475, lambrolizumab, CAS Reg. No. 1374853-91-4), as well as
the PD-1 blocking agents described in U.S. Pat. Nos. 7,488,802,
7,943,743, 8,008,449, 8,168,757, 8,217,149, WO 03042402, WO
2008156712, WO 2010089411, WO 2010036959, WO 2011066342, WO
2011159877, WO 2011082400, and WO 2011161699; b) Inhibitors of
Programmed Death--Ligand 1 (PD-L1, also known as B7-H1 and CD274),
including antibodies such as BMS-936559, MPDL3280A), MEDI4736,
MSB0010718C, and MDX1105-01); also including: atezolizumab,
durvalumab and avelumab; c) Inhibitors of CTLA-4, such as
ipilimumab (YERVOY.RTM., MDX-010, BMS-734016, and MDX-101),
tremelimumab, antibody clone BNI3 (Abeam), RNA inhibitors,
including those described in WO 1999/032619, WO 2001/029058, U.S.
2003/0051263, U.S. 2003/0055020, U.S. 2003/0056235, U.S.
2004/265839, U.S. 2005/0100913, U.S. 2006/0024798, U.S.
2008/0050342, U.S. 2008/0081373, U.S. 2008/0248576, U.S.
2008/055443, U.S. Pat. Nos. 6,506,559, 7,282,564, 7,538,095 and
7,560,438 (each incorporated herein by reference); d) inhibitors of
PD-L2 (B7-DC, CD273), such as AMP-224 (Amplimune, Inc.) and
rHIgM12B7; and e) Inhibitors of checkpoint proteins, including:
LAG3, such as IMP321; TIM3 (HAVCR2); 2B4; A2aR, ID02; B7H1; B7-H3
or B7H3, such as antibody MGA271; B7H4; BTLA; CD2; CD20, such as
ibritumomab tiuxetan, ofatumumab, rituximab, obinutuzumab and
tositumomab; CD27, such as CDX-1127; CD28; CD3O, such as
brentuximab vedotin; CD33, such as gemtuzumab ozogamicin; CD40;
CD52, such as alemtuzumab; CD70; CD80; CD86; CD112; CD137; CD160;
CD226; CD276; DR3; OX-40 (TNFRSF.sub.4 and CD134); GAL9; GITR; such
as TRX518; HAVCR2; HVEM; ID01; ICOS (inducible T cell costimulator;
CD278); such as MEDI570 (Medimmune LLC) and AMG557 (Amgen); KIR;
LAIR; LIGHT; MARCO (macrophage receptor with collageneous
structure); PS (phosphatidylserine); SLAM; TIGIT; VISTA; and VTCNI;
or a combinations thereof. In another variation, the checkpoint
inhibitor is an inhibitor of a checkpoint protein selected from the
group of PD-1, PD-L1 and CTLA-4. In another variation, the
checkpoint inhibitor is selected from the group of an anti-PD-1
antibody, and anti-PD-L1 antibody and an anti-CTLA-4 antibody. In
one variation, the anti-PD-1 antibody is selected from the group of
nivolumab, pembrolizumab, and lambrolizumab. In another variation,
the anti-PD-L1 antibody is selected from the group of as
BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01. In
yet other variations, the anti-PD-L1 antibody is selected from the
group of durvalumab, atezolizumab, and avelumab, In another
variation, the anti-CTLA-4 antibody is selected from the group of
ipilimumab and tremelimumab. In one embodiment, the check point
inhibitor is selected from the group consisting of nivolumab,
pembrolizumab, lambrolizumab, BMS-936559, MPDL3280A, MEDI4736,
MSB0010718C, MDX1105-01, durvalumab, atezolizumab, avelumab,
ipilimumab, and tremelimumab. In certain embodiment, the check
point inhibitor is selected from the group consisting of nivolumab,
pembrolizumab, lambrolizumab, durvalumab, atezolizumab, avelumab,
ipilimumab, and tremelimumab. In one embodiment, the check point
inhibitor is selected from the group consisting of nivolumab,
pembrolizumab, durvalumab, atezolizumab, and avelumab. Said
checkpoint inhibitors listed may be administered via multiple
methods, including but not limited intravenously, intramuscularly,
parenterally, nasally, intratumorally, intraosseously,
subcutaneously, sublingually, intrarectally, intrathecally,
intraventricularly, orally, intra-ocular, topically, or via
inhalation, nanocell and/or nanobubble injection. For practices of
the invention, the enhancement of efficacy of an immune checkpoint
inhibitor may be accomplished by performing one or more clinical
procedures involving the removal of tumor derived blocking factors
to prepare and/or condition the patient. Said removal may be
performed at various time points prior to administration of said
checkpoint inhibitor(s). The determination of time points of
removal, in some embodiments, is performed based on immunological
and/or oncological assessment of the patient. In some situations,
immune activity of the patient assessed, and used as a basis for
determining the amount and frequency of extracorporeal treatments
prior to administration of checkpoint inhibitors. In some
situations, it may be desirable to continue extracorporeal
treatments while administering checkpoint inhibitors, Furthermore,
in some situations it may be desirable to continue extracorporeal
treatment following administration of checkpoint inhibitors.
[0044] In some embodiments, checkpoint inhibitor drugs are
increased in efficacy by removal of extracorporeal blocking
factors. Said checkpoint inhibitor may be used to further increase
in efficacy by addition of one or more cancer vaccines, which is
referred to as "active immunization". In some embodiments of the
invention, administration of checkpoint inhibitors is performed
together with active immunization. Immunization may take the form
of peptides, proteins, altered peptide ligands, and cell
therapy,
[0045] Antigens known to be found on cancer, and useful for the
practice of the invention include: epidermal growth factor receptor
(EGFR, EGFR1, ErbB-1, HER1); ErbB-2 (HER2/neu), ErbB-3/HER3,
ErbB-4/HER4, EGFR ligand family; insulin-like growth factor
receptor (IGFR) family, IGF-binding proteins (IGFBPs), IGFR ligand
family (IGF-1R); platelet derived growth factor receptor (PDGFR)
family, PDGFR ligand family; fibroblast growth factor receptor
(FGFR) family, FGFR ligand family, vascular endothelial growth
factor receptor (VEGFR) family, VEGF family; HGF receptor family;
TRK receptor family; ephrin (EPH) receptor family; AXL receptor
family; leukocyte tyrosine kinase (LTK) receptor family; TIE
receptor family, angiopoietin 1, 2; receptor tyrosine kinase-like
orphan receptor (ROR) receptor family; discoidin domain receptor
(DDR) family; RET receptor family; KLG receptor family; RYK
receptor family; MuSK receptor family; transforming growth factor
alpha (TGF-alpha), TGF-alphareceptor; transforming growth
factor-beta (TGF-beta), TGF-beta receptor; interleukin beta
receptor alpha2 chain (IL13Ralpha2); interleukin-6 (IL-6), IL-6
receptor; interleukin-4. IL-4 receptor; cytokine receptors, Class I
(hematopoietin family) and Class II (interferon/1L-10 family)
receptors; tumor necrosis factor (TNF) family, TNF-alpha; tumor
necrosis factor (TNF) receptor superfamily (TNTRSF); death receptor
family, TRAIL-receptor; cancer-testis (CT) antigens;
lineage-specific antigens; differentiation antigens;
alpha-actinin-4; ARTC1, breakpoint cluster region--Abelson
(Bcr-abl) fusion products; B-RAF; caspase-5 (GASP-5); caspase-8
(CASP-8); beta-catenin (CTNNB1); cell division cycle 27 (CDC27);
cyclin-dependent kinase 4 (CDK4); CDKN2A; COA-1; dek-can fusion
protein; EFTUD-2; Elongation factor 2 (ELF2); Ets variant gene
6/acute myeloid leukemia 1 gene EFS (ETC6-AML1) fusion protein;
fibronectin (FN); GPNMB; low density lipid receptor/GDP-L fucose;
beta-D-galactose 2-alpha-Lfucosyltraosferase (LDLR/FUT) fusion
protein; HLA-A2; MLA-A11; heat shock protein 70-2 mutated
(HSP70-2M); KIAA0205; MART2; melanoma ubiquitous mutated 1, 2, 3
(MUM-1, 2, 3); prostatic acid phosphatase (PAP); neo-PAP; Myosin
class 1; NFYC; OGT, OS-9; pml-RARalpha fusion protein; PRDX5;
PTPRK. K-ras (KRAS2); N-ras (NRAS); HRAS; RBAF600; SIRT12; SNRPD1;
SYT-SSX1 or -SSX2 fusion protein; Triosephosphate Isomerase; BAGE;
BAGE-1; BAGE-2, 3, 4, 5; GAGE-1, 2, 3, 4, 5, 6, 7, 8; GnT-V
(aberrant N-acetyl glucosaminyl transferase V; MGAT5), HERV-K MEL,
KK-LC, KM-I4N-1, LAGE, LAGE-1, CTL-recognized antigen on melanoma
(CAMEL), MAGE-A1 (MAGE-1); MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A5;
MAGE-A6; MAGE-A8; MAGE-A9; MAGE-A10; MAGE-A11; MAGE-A12; MAGE-3;
MAGE-B1; MAGE-B2; MAGE-B5; MAGE-B6; MAGE-C1; MAGE-C2; mucin 1
(MUC1); MART-1/Melan-A (MLANA); gp100; gp100/Pme117 (SILV);
tyrosinase (TYR); TRP-1; HAGE; NA-88; NY-ESO-1; NY-ESO-1/LAGE-2;
SAGE, Sp17; SSX-1, 2, 3, 4; TRP2-1NT2; carcino-embryonic antigen
(CEA); Kallikrein 4; mammaglobin-A; OA1; prostate specific antigen
(PSA); prostate specific membrane antigen; TRP-1/, 75; TRP-2
adipophilin; interferon inducible protein absent in melanoma 2
(AIM-2); BING-4; CPSF; cyclin D1; epithelial cell adhesion molecule
(Ep-CAM); EpbA3; fibroblast growth factor-5 (FGF-5); glycoprotein
250 (gp250 intestinal carboxyl esterase (iCE); alpha-feto protein
(AFP); M-CSF; mdm-2; MUCI; p53 (TP53); PBF; PRAME; PSMA; RAGE-1;
RNF43; RU2AS; SOX10; STEAP1; survivin (BIRCS); human telomerase
reverse transcriptase (hTERT); telomerase; Wilms' tumor gene (WT1);
SYCP1; BRDT; SPANX; XAGE; ADAM2; PAGE-5; LIP1; CTAGE-1; CSAGE;
MMA1; CAGE; BORIS; HOM-TES-85; AF15q14; HCA661; LDHC; MORC; SGY-1;
SPO11; TPX1; NY-SAR-35; FTHL17; NXF2 TDRD1; TEX 15; FATE; TPTE;
immunoglobulin idiotypes; Bence-Jones protein; estrogen receptors
(ER); androgen receptors (AR); CD40; CD30; CD20; CD19; CD33; CD4;
CD25; CD3; cancer antigen 72-4 (CA 72-4); cancer antigen 15-3 (CA
15-3); cancer antigen 27-29 (CA 27-29); cancer antigen 125 (CA
125); cancer antigen 19-9 (CA 19-9); beta-human chorionic
gonadotropin; 1-2 microglobulin; squamous cell carcinoma antigen;
neuron-specific enolase; heat shock protein gp96; GM2,
sargramostim; CTLA-4; 707 alanine proline (707-AP); adenocarcinoma
antigen recognized by T cells 4 (ART-4); carcinoembryogenic antigen
peptide-1 (CAP-1); calcium-activated chloride channel-2 (CLCA2);
cyclophilin B (Cyp-B); and human signet ring tumor-2 (HST-2).
[0046] In one embodiment, the invention teaches the use of removal
of extracorporeal blocking factors to increase the number of
dendritic cells infiltrating tumors. The utilization of dendritic
cells as an immunotherapy is known in the art and ways of using
dendritic cell therapy are defined in the following examples for
melanoma [67-118], soft tissue sarcoma [119], thyroid [120-122],
glioma [123-144], multiple myeloma ,[145-153], lymphoma [154-156],
leukemia [157-164], as well as liver [165-170], lung [171-184],
ovarian [185-188], and pancreatic cancer [189-191]. In other
embodiments the invention teaches the use of extracorporeal removal
of immunological blocking factors for augmentation of existing
dendritic cells to infiltrate tumors. Means of assessing dendritic
cell infiltration are known in the art and described in the
following examples: for gastric cancer [192-195], head and neck
cancer [196-200], cervical cancer [201], breast cancer [202-204],
lung cancer [205], colorectal cancer [206-208], liver cancer [209,
210], gall bladder cancer [211, 212], and pancreatic cancer
[213].
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