U.S. patent application number 17/645391 was filed with the patent office on 2022-04-14 for checkpoint inhibitor and a whole cell mycobacterium for use in cancer therapy.
The applicant listed for this patent is IMMODULON THERAPEUTICS LIMITED. Invention is credited to CHARLES AKLE, LAURA ROSA BRUNET.
Application Number | 20220111046 17/645391 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-14 |
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United States Patent
Application |
20220111046 |
Kind Code |
A1 |
AKLE; CHARLES ; et
al. |
April 14, 2022 |
CHECKPOINT INHIBITOR AND A WHOLE CELL MYCOBACTERIUM FOR USE IN
CANCER THERAPY
Abstract
An immunomodulator for use in the treatment, reduction,
inhibition or control of a neoplastic disease in a patient intended
to undergo checkpoint inhibition therapy, selected from a cell,
protein, peptide, antibody or antigen binding fragment thereof,
directed against CTLA-4, PD-1, PD-L1 and combinations thereof,
simultaneously, separately or sequentially with administration of
the immunomodulator. The immunomodulator comprises a whole cell
Mycobacterium, for example, M. vaccae or M. obuense.
Inventors: |
AKLE; CHARLES; (UXBRIDGE,
GB) ; BRUNET; LAURA ROSA; (UXBRIDGE, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IMMODULON THERAPEUTICS LIMITED |
LONDON |
|
GB |
|
|
Appl. No.: |
17/645391 |
Filed: |
December 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15738674 |
Dec 21, 2017 |
11207405 |
|
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PCT/GB2016/051893 |
Jun 24, 2016 |
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17645391 |
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International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 9/00 20060101 A61K009/00; A61K 35/74 20060101
A61K035/74; A61P 35/00 20060101 A61P035/00; C07K 16/28 20060101
C07K016/28 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 24, 2015 |
GB |
1511120.6 |
Jun 24, 2015 |
GB |
1511121.4 |
Claims
1. A method for use in the treatment, reduction, inhibition or
control of neoplasia, tumour and/or cancer in a subject, wherein
said method comprises administering to the subject, (i) a
checkpoint inhibitor comprising an antibody selected from
MEDI-4736, MSB001078C, BMS-986016, MGA-271, MEDI-0680, or
tremelimumab, or combinations thereof, and (ii) an immunomodulator,
wherein said method results in enhanced therapeutic efficacy
relative to administration of the checkpoint inhibitor or
immunomodulator alone, wherein said immunomodulator comprises whole
cell, non-pathogenic heat-killed Mycobacterium obuense and wherein
said immunomodulator is administered simultaneously, separately or
sequentially with administration of the checkpoint inhibitor.
2. The method according to claim 1, wherein said checkpoint
inhibitor comprises MSB001078C.
3. The method according to claim 1, wherein said cancer is selected
from prostate cancer, liver cancer, renal cancer, lung cancer,
breast cancer, colorectal cancer, pancreatic cancer, brain cancer,
hepatocellular cancer, lymphoma, leukaemia, gastric cancer,
cervical cancer, ovarian cancer, thyroid cancer, melanoma, head and
neck cancer, skin cancer or soft tissue sarcoma.
4. The method according to claim 3, wherein said cancer is selected
from melanoma, pancreatic, colorectal, prostate or ovarian
cancer.
5. The immunomodulator for use according to claim 1, wherein said
cancer is metastatic.
6. The method according to claim 1, wherein said whole cell,
non-pathogenic heat-killed Mycobacterium obuense is the rough
variant.
7. The method according to claim 6, wherein said whole cell,
non-pathogenic heat-killed Mycobacterium obuense and/or checkpoint
inhibitor is administered via the parenteral, oral, sublingual,
nasal or pulmonary route.
8. The method according to claim 7, wherein the parenteral route is
selected from subcutaneous, intradermal, subdermal,
intraperitoneal, or intravenous.
9. The method according to claim 7, wherein the parenteral route
comprises intratumoural injection or administration adjacent to
tumours or adjacent to lymph nodes.
10. The method according to claim 1, wherein the amount of whole
cell, non-pathogenic heat-killed Mycobacterium obuense administered
per dose is from 10.sup.7 to 10.sup.9 cells, or preferably from 0.1
mg to 1 mg organisms.
11. The method according to claim 1, wherein the enhanced
therapeutic efficacy is measured by increased overall survival
time.
12. The method according to claim 1, wherein the enhanced
therapeutic efficacy is measured by increased progression free
survival.
13. The method according to claim 1, wherein the enhanced
therapeutic efficacy is measured by a decrease or stabilisation of
tumour size.
14. The method according to claim 1, wherein the enhanced
therapeutic efficacy is measured by an improved overall response
rate and/or increased quality of life.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/738,674, filed Dec. 21, 2017, which is the
National Stage of International Application Number
PCT/GB2016/051893, filed Jun. 24, 2016, each of which is hereby
incorporated by reference herein in its entirety, including any
figures, tables, nucleic acid sequences, amino acid sequences, or
drawings.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of cancer
therapy. In particular, the present invention relates to a method
of preventing, treating or inhibiting the development of tumours
and/or metastases in a subject.
BACKGROUND OF THE INVENTION
[0003] In humans with advance cancer, anti-tumour immunity is often
ineffective due to the tightly regulated interplay of pro- and
anti-inflammatory, immune-stimulatory and immunosuppressive
signals. For example, loss of the anti-inflammatory signals leads
to chronic inflammation and prolonged proliferative signalling.
Interestingly, cytokines that both promote and suppress
proliferation of the tumour cells are produced at the tumour site.
It is the imbalance between the effects of these various processes
that results in tumour promotion.
[0004] To date, a major barrier to attempts to develop effective
immunotherapy for cancer has been an inability to break
immunosuppression at the cancer site and restore normal networks of
immune reactivity. The physiological approach of immunotherapy is
to normalize the immune reactivity so that, for example, the
endogenous tumour antigens would be recognized and effective
cytolytic responses would be developed against tumour cells.
Although it was once unclear if tumour immunosurveillance existed,
it is now believed that the immune system constantly monitors and
eliminates newly transformed cells. Accordingly, cancer cells may
alter their phenotype in response to immune pressure in order to
escape attack (immunoediting) and upregulate expression of
inhibitory signals. Through immunoediting and other subversive
processes, primary tumour and metastasis maintain their own
survival.
[0005] One of the major mechanisms of anti-tumour immunity
subversion is known as `T-cell exhaustion`, which results from
chronic exposure to antigens and is characterized by the
up-regulation of inhibitory receptors. These inhibitory receptors
serve as immune checkpoints in order to prevent uncontrolled immune
reactions.
[0006] PD-1 and co-inhibitory receptors such as cytotoxic
T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator
(BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3),
Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often
referred to as a checkpoint regulators. They act as molecular
"tollbooths," which allow extracellular information to dictate
whether cell cycle progression and other intracellular signalling
processes should proceed.
[0007] In addition to specific antigen recognition through the TCR,
T-cell activation is regulated through a balance of positive and
negative signals provided by co-stimulatory receptors. These
surface proteins are typically members of either the TNF receptor
or B7 superfamilies. Agonistic antibodies directed against
activating co-stimulatory molecules and blocking antibodies against
negative co-stimulatory molecules may enhance T-cell stimulation to
promote tumour destruction.
[0008] Programmed Cell Death Protein 1, (PD-1 or CD279), a 55-kD
type 1 transmembrane protein, is a member of the CD28 family of T
cell co-stimulatory receptors that include immunoglobulin
superfamily member CD28, CTLA-4, inducible co-stimulator (ICOS),
and BTLA. PD-1 is highly expressed on activated T cells and B
cells. PD-1 expression can also be detected on memory T-cell
subsets with variable levels of expression. Two ligands specific
for PD-1 have been identified: programmed death-ligand 1 (PD-L1,
also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or
CD273). PD-L1 and PD-L2 have been shown to down-regulate T cell
activation upon binding to PD-1 in both mouse and human systems
(Okazaki et al., Int Immunol., 2007; 19: 813-824). The interaction
of PD-1 with its ligands, PD-L1 and PD-L2, which are expressed on
antigen-presenting cells (APCs) and dendritic cells (DCs),
transmits negative regulatory stimuli to down-modulate the
activated T cell immune response. Blockade of PD-1 suppresses this
negative signal and amplifies T cell responses. Numerous studies
indicate that the cancer microenvironment manipulates the
PD-L1-/PD-1 signalling pathway and that induction of PD-L1
expression is associated with inhibition of immune responses
against cancer, thus permitting cancer progression and metastasis.
The PD-L1/PD-1 signalling pathway is a primary mechanism of cancer
immune evasion for several reasons. First, and most importantly,
this pathway is involved in negative regulation of immune responses
of activated T effector cells, found in the periphery. Second,
PD-L1 is up-regulated in cancer microenvironments, while PD-1 is
also up-regulated on activated tumour infiltrating T cells, thus
possibly potentiating a vicious cycle of inhibition. Third, this
pathway is intricately involved in both innate and adaptive immune
regulation through bi-directional signalling. These factors make
the PD-1/PD-L1 complex a central point through which cancer can
manipulate immune responses and promote its own progression.
[0009] The first immune-checkpoint inhibitor to be tested in a
clinical trial was ipilimumab (Yervoy, Bristol-Myers Squibb), a
CTLA-4 mAb. CTLA-4 belongs to the immunoglobulin superfamily of
receptors, which also includes PD-1, BTLA, TIM-3, and V-domain
immunoglobulin suppressor of T cell activation (VISTA).
[0010] Anti-CTLA-4 mAb is a powerful checkpoint inhibitor which
removes "the break" from both naive and antigen-experienced cells.
Therapy enhances the antitumor function of CD8+ T cells, increases
the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and
inhibits the suppressive function of T regulatory cells. The major
drawback to anti-CTLA-4 mAb therapy is the generation of autoimmune
toxicities due to on-target effects of an over-exuberant immune
system which has lost the ability to turn itself down. It has been
reported that up to 25% of patients treated with ipilimumab
developed serious grade 3-4 adverse events/autoimmune-type side
effects including dermatitis, enterocolitis, hepatitis,
endocrinopathies (including hypophysitis, thyroiditis, and
adrenalitis), arthritis, uveitis, nephritis, and aseptic
meningitis. In contrast to the anti-CTLA-4 experience, anti-PD-1
therapy appears to be better-tolerated and induces a relatively
lower rate of autoimmune-type side effects.
[0011] TIM-3 has been identified as another important inhibitory
receptor expressed by exhausted CD8+ T cells. In mouse models of
cancer, it has been shown that the most dysfunctional
tumour-infiltrating CD8+ T cells actually co-express PD-1 and
TIM-3.
[0012] LAG-3 is another recently identified inhibitory receptor
that acts to limit effector T-cell function and augment the
suppressive activity of T regulatory cells. It has recently been
revealed that PD-1 and LAG-3 are extensively co-expressed by
tumour-infiltrating T cells in mice, and that combined blockade of
PD-1 and LAG-3 provokes potent synergistic antitumor immune
responses in mouse models of cancer.
[0013] PD-1 pathway blockade can be combined with vaccines or other
immunomodulatory antibodies for improved therapeutic efficacy
(Hirano, F. et al, Cancer Res., 65(3): 1089-1096 (2005); Li, B. et
al, Clin. Cancer Res., 15: 1507-1509 (2009); and Curran, M. A. et
al, Proc. Natl. Acad. Set, 107(9):4275-4280 (2010)).
[0014] Currently, antagonist mAbs against both PD-1 and their
ligand PD-L1 are in various stages of development for the treatment
of cancer, and recent human trials have shown promising results in
cancer patients with advanced, treatment-refractory disease.
[0015] The first of the agents blocking the B7-H1/PD-1 pathway to
enter phase I clinical trials was Nivolumab
(MDX-1106/BMS-936558/ONO-4538), a fully human IgG4 anti-PD-1 mAb
developed by Bristol-Myers Squibb. Another PD-1 mAb undergoing
clinical evaluation is CT-011, a humanized IgG1 mAb specific for
PD-1 developed by CureTech Ltd. Other agents include Lambrolizumab
(MK-3475--Merck), a humanized monoclonal IgG4 PD-1 antibody;
BMS-936559, a fully human IgG4 PD-L1 antibody and Roche's
MPDL3280A, a human monoclonal antibody that targets the PD-L1
pathway.
[0016] The results of a phase H study that compared combined
nivolumab and ipilimumab with ipilimumab alone in patients with
BRAF wild-type melanoma showed objective response rates of 61% with
the combination therapy and 11% with the monotherapy, with complete
responses in 22% and 0% of patients. respectively.
http:www.nejm.org/dol/full.10.1056/NEJMoa1504030.ref13
Treatment-related adverse events of grade 3 or 4 were reported in
54% of the patients in the combination group and in 24% of those in
the ipilimumab group. Treatment-related adverse events of any grade
that led to discontinuation of the study drug occurred in 7.7% of
the patients in the nivolumab group, 36.4% of those in the
nivolumab-plus-ipilimumab group, and 14.8% of those in the
ipilimumab group.
[0017] Accordingly, an aim of the present invention is a
combination therapy for treating cancer comprising an
immunomodulator and blockade of checkpoint inhibitors with the
potential to elicit potent and durable immune responses.
[0018] Another aim of the present invention is a combination
therapy for treating cancer comprising an immunomodulator and
blockade of checkpoint inhibitors with the potential to reduce
treatment-related adverse events.
SUMMARY OF THE INVENTION
[0019] The present invention provides an effective method for
treating and/or preventing cancer and/or the establishment of
metastases by administering a checkpoint inhibitor which acts
synergistically with a whole cell non-pathogenic heat-killed
Mycobacterium.
[0020] In a first aspect of the invention, there is an
immunomodulator for use in the treatment, reduction, inhibition or
control of cancer in a patient intended to undergo checkpoint
inhibition therapy, and wherein said checkpoint inhibition therapy
comprises administration of a blocking agent, selected from a cell,
protein, peptide, antibody or antigen binding fragment thereof,
directed against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4,
B7-H6, A2AR, or IDO, and combinations thereof, wherein the
immunomodulator comprises a whole cell, non-pathogenic heat-killed
Mycobacterium and wherein said immunomodulator is to be
administered simultaneously, separately or sequentially with
administration of the checkpoint inhibition therapy, optionally
wherein said checkpoint inhibition therapy comprises administration
of a sub-therapeutic amount and/or duration of said blocking
agent.
[0021] In a second aspect of the invention, there is a method of
treating, reducing, inhibiting or controlling a neoplasia, tumour
or cancer in a subject, wherein said method comprises
simultaneously, separately or sequentially administering to the
subject, (i) a checkpoint inhibitor, selected from a cell, protein,
peptide, antibody or antigen binding fragment thereof, directed
against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6,
A2AR, or IDO, and combinations thereof, and (ii) an
immunomodulator, wherein said method results in enhanced
therapeutic efficacy relative to administration of the checkpoint
inhibitor or immunomodulator alone, and wherein the immunomodulator
comprises a whole cell, non-pathogenic heat-killed Mycobacterium,
and optionally wherein said method comprises administration of a
sub-therapeutic amount of said checkpoint inhibitor.
[0022] The present invention therefore provides a combination
therapy of checkpoint inhibitor therapy together with a specific
type of immunotherapy comprising administration of an
immunomodulator. The inventors have found that the combination of
both therapies is synergistic beyond simple additive effects of
each therapy used individually.
DESCRIPTION OF THE DRAWINGS
[0023] The invention is described with reference to the following
drawings, in which:
[0024] FIG. 1 shows the effect of a preparation of heat-killed
Mycobacterium obuense (NCTC 13365) with or without
co-administration of a checkpoint inhibitor (ant-PD-L1 mAb), in a
xenograft model of pancreatic cancer (KPC cells injected
subcutaneously).
[0025] FIG. 2--is as above except that the co-administered
checkpoint inhibitor is an anti-PD-1 mAb.
[0026] FIG. 3 shows the ratio of CD3+CD8+ cells and FoxP3 Treg
cells infiltrating the tumours in control mice (red), mice that
have received anti-CTLA-4 treatment only (blue) or mice that have
received combination treatment consisting of IMM-101 and
anti-CTLA-4 (green). We found a significant increase (Anova
p<0.05) in this group.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The invention provides a method for treating, reducing,
inhibiting or controlling a neoplasia, tumour or cancer in a
subject involving administering an immunomodulator and a checkpoint
inhibitor. It is based upon the discovery that administration of an
immunomodulator (whole cell heat-killed Mycobacterium) in
combination with a checkpoint inhibitor directed against PD-L1,
PD-1, CTLA-4, PD-L2, CAG-3, B7-H3, B7-H4, B7-H6, A2AR or IDO
results in synergistic anti-tumour activity and/or antitumor
activity that is more potent than administration of immunomodulator
or checkpoint inhibitor alone.
[0028] It is preferred that the checkpoint inhibitor for use in the
present invention is one directed against PD-L1, PD-1 or CTLA-4.
For example, the inhibitor may be directed against PD-L1.
[0029] In order that the present invention may be more readily
understood, certain terms are first defined. Additional definitions
are set forth throughout the detailed description.
[0030] A "checkpoint inhibitor" is an agent which acts on surface
proteins which are members of either the TNF receptor or B7
superfamilies, including agents which bind to negative
co-stimulatory molecules selected from CTLA-4, PD-1, TIM-3, BTLA,
VISTA, LAG-3, and/or their respective ligands, including PD-L1.
(Mellman et al., supra). A "blocking agent" is an agent which
either binds to the above co-stimulatory molecules and/or their
respective ligands. "Checkpoint inhibitor" and "blocking agent" are
used interchangeably throughout. The inhibitor is preferably an
antibody or antigenic-binding molecule that targets an antigenic
site on the surface proteins. For example, the inhibitor is an
antibody that targets an antigenic site on PD-L1, or PD-1 or
CTLA-4.
[0031] An immunomodulator, as defined according to the present
invention, is a component which stimulates innate and type-1
immunity, including Th1 and macrophage activation and cytotoxic
cell activity, as well as independently down-regulating
inappropriate anti-Th2 responses via immunoregulatory
mechanisms.
[0032] The terms "tumour," "cancer" and "neoplasia" are used
interchangeably and refer to a cell or population of cells whose
growth, proliferation or survival is greater than growth,
proliferation or survival of a normal counterpart cell, e.g. a cell
proliferative or differentiative disorder. Typically, the growth is
uncontrolled. The term "malignancy" refers to invasion of nearby
tissue. The term "metastasis" refers to spread or dissemination of
a tumour, cancer or neoplasia to other sites, locations or regions
within the subject, in which the sites, locations or regions are
distinct from the primary tumour or cancer.
[0033] The terms "Programmed Death 1," "Programmed Cell Death 1,"
"Protein PD-1," "PD-1," and "PD1," are used interchangeably, and
include variants, isoforms, species homologs of human PD-1, and
analogs having at least one common epitope with PD-1. The complete
PD-1 sequence can be found under GenBank Accession No. U64863.
[0034] The terms "CD27," and "CD27 antigen" are used
interchangeably, and include variants, isoforms, species homologs
of human CD27, and analogs having at least one common epitope with
CD27 (see, e.g., Hendriks (2000) Nat Immumol. 171 (5). 433-40.)
[0035] The terms "B7-H3" and "CD276" are used interchangeably, and
include variants, isoforms, species homologs of human B7-H3, and
analogs having at least one common epitope with B7-H3 (see e.g.
Wilcox et al., (2012) Eur. J. Haematology; 88.465-475).
[0036] The terms "B7-H4" and "VTCN1" are used interchangeably, and
include variants, isoforms, species homologs of human B7-H4, and
analogs having at least one common epitope with B7-H4 (Wilcox
supra).
[0037] The terms "A2AR" and "Adenosine A2A receptor" are used
interchangeably, and include variants, isoforms, species homologs
of human A2AR, and analogs having at least one common epitope with
A2AR.
[0038] The terms "IDO" and "Indoleamine 2,3-dioxygenase" are used
interchangeably, and include variants, isoforms, species homologs
of human IDO, and analogs having at least one common epitope with
IDO.
[0039] The terms "cytotoxic T lymphocyte-associated antigen-4,"
"CTLA-4," "CTLA4," and "CTLA-4 antigen" (see, e.g., Murata, Am. J.
Pathol. (1999) 155:453-460) are used interchangeably, and include
variants, isoforms, species homologs of human CTLA-4, and analogs
having at least one common epitope with CTLA-4 (see, e.g., Balzano
(1992) Int. J. Cancer Suppl. 7:28-32). The complete CTLA-4 nucleic
acid sequence can be found under GenBank Accession No. L15006.
[0040] As used herein, "sub-therapeutic dose" means a dose of a
therapeutic compound (e.g., an antibody) or duration of therapy
which is lower than the usual or typical dose of the therapeutic
compound or therapy of shorter duration, when administered alone
for the treatment of cancer.
[0041] The term "therapeutically effective amount" is defined as an
amount of a checkpoint inhibitor, in combination with an
immunomodulator, that preferably results in a decrease in severity
of disease symptoms, an increase in frequency and duration of
disease symptom-free periods, or a prevention of impairment or
disability due to the disease affliction. The terms "effective
amount" or "pharmaceutically effective amount" refer to a
sufficient amount of an agent to provide the desired biological or
therapeutic result. That result can be reduction, amelioration,
palliation, lessening, delaying, and/or alleviation of one or more
of the signs, symptoms, or causes of a disease, or any other
desired alteration of a biological system. In reference to cancer,
an effective amount may comprise an amount sufficient to cause a
tumour to shrink and/or to decrease the growth rate of the tumour
(such as to suppress tumour growth) or to prevent or delay other
unwanted cell proliferation. In some embodiments, an effective
amount is an amount sufficient to delay development, or prolong
survival or induce stabilisation of the cancer or tumour.
[0042] In some embodiments, a therapeutically effective amount is
an amount sufficient to prevent or delay recurrence. A
therapeutically effective amount can be administered in one or more
administrations. The therapeutically effective amount of the drug
or combination may result in one or more of the following: (i)
reduce the number of cancer cells; (ii) reduce tumour size; (iii)
inhibit, retard, slow to some extent and preferably stop cancer
cell infiltration into peripheral organs; (iv) inhibit (i.e., slow
to some extent and preferably stop) tumour metastasis; (v) inhibit
tumour growth; (vi) prevent or delay occurrence and/or recurrence
of tumour; and/or (vii) relieve to some extent one or more of the
symptoms associated with the cancer.
[0043] For example, for the treatment of tumours, a
"therapeutically effective dosage" may induce tumour shrinkage by
at least about 5% relative to baseline measurement, such as at
least about 10%, or about 20%, or about 60% or more. The baseline
measurement may be derived from untreated subjects.
[0044] A therapeutically effective amount of a therapeutic compound
can decrease tumour size, or otherwise ameliorate symptoms in a
subject. One of ordinary skill in the art would be able to
determine such amounts based on such factors as the subject's size,
the severity of the subject's symptoms, and the particular
composition or route of administration selected.
[0045] The term "immune response" refers to the action of, for
example, lymphocytes, antigen presenting cells, phagocytic cells,
granulocytes, and soluble macromolecules produced by the above
cells or the liver (including antibodies, cytokines, and
complement) that results in selective damage to, destruction of, or
elimination from the human body of cancerous cells.
[0046] The term "antibody" as referred to herein includes whole
antibodies and any antigen-binding fragment (i.e., "antigen-binding
portion") or single chains thereof.
[0047] The term "antigen-binding portion" of an antibody (or simply
"antibody portion"), as used herein, refers to one or more
fragments of an antibody that retain the ability to specifically
bind to a receptor and its ligand (e.g., PD-1). including:(i) a Fab
fragment, (ii) a F(ab') 2 fragment,; (iii) a Fd fragment consisting
of the VH and CHI domains; (iv) a Fv fragment, (v) a dAb fragment
(Ward et al, Nature, 341:544-546 (1989)), which consists of a VH
domain; and (vi) an isolated complementarity determining region
(CDR). Single chain antibodies are also intended to be encompassed
within the term "antigen-binding portion" of an antibody. These
antibody fragments are obtained using conventional techniques known
to those with skill in the art, and the fragments are screened for
utility in the same manner as are intact antibodies.
[0048] The terms "monoclonal antibody" or "monoclonal antibody
composition" as used herein refer to a preparation of antibody
molecules of single molecular composition.
[0049] A monoclonal antibody composition displays a single binding
specificity and affinity for a particular epitope.
[0050] The term "human antibody", as used herein, is intended to
include antibodies having variable regions in which both the
framework and CDR regions are derived from human germline
immunoglobulin sequences.
[0051] The term "humanized antibody" is intended to refer to
antibodies in which CDR sequences derived from the germline of
another mammalian species, such as a mouse, have been grafted onto
human framework sequences. Additional framework region
modifications may be made within the human framework sequences.
[0052] In addition to antibodies, other biological molecules may
act as checkpoint inhibitors, including peptides having binding
affinity to the appropriate target.
[0053] The term "treatment" or "therapy" refers to administering an
active agent with the purpose to cure, heal, alleviate, relieve,
alter, remedy, ameliorate, improve, or affect a condition (e.g., a
disease), the symptoms of the condition, or to prevent or delay the
onset of the symptoms, complications, biochemical indicia of a
disease, or otherwise arrest or inhibit further development of the
disease, condition, or disorder in a statistically significant
manner.
[0054] As used herein, the term "subject" is intended to include
human and non- human animals. Preferred subjects include human
patients in need of enhancement of an immune response. The methods
are particularly suitable for treating human patients having a
disorder that can be treated by augmenting the T-cell mediated
immune response. In a particular embodiment, the methods are
particularly suitable for treatment of cancer cells in vivo.
[0055] As used herein, the terms "concurrent administration" or
"concurrently" or "simultaneous" mean that administration occurs on
the same day. The terms "sequential administration" or
"sequentially" or "separate" mean that administration occurs on
different days.
[0056] "Simultaneous" administration, as defined herein, includes
the administration of the immunomodulator and agent or procedure
comprising checkpoint inhibitor therapy within about 2 hours or
about 1 hour or less of each other, even more preferably at the
same time.
[0057] "Separate" administration, as defined herein, includes the
administration of the immunomodulator and agent or procedure
comprising checkpoint inhibitor therapy, more than about 12 hours,
or about 8 hours, or about 6 hours or about 4 hours or about 2
hours apart.
[0058] "Sequential" administration, as defined herein, includes the
administration of the immunomodulator and chemotherapeutic agent
each in multiple aliquots and/or doses and/or on separate
occasions. The immunomodulator may be administered to the patient
after before and/or after administration of the checkpoint
inhibitor. Alternatively, the immunomodulator is continued to be
applied to the patient after treatment with a checkpoint
inhibitor.
[0059] The use of the alternative (e.g., "or") should be understood
to mean either one, both, or any combination thereof of the
alternatives. As used herein, the indefinite articles "a" or "an"
should be understood to refer to "one or more" of any recited or
enumerated component.
[0060] As used herein, "about" means within an acceptable error
range for the particular value as determined by one of ordinary
skill in the art, which will depend in part on how the value is
measured or determined, i.e., the limitations of the measurement
system. For example, "about" can mean within 1 or more than 1
standard deviation per the practice in the art. Alternatively,
"about" can mean a range of up to 20%. When particular values are
provided in the application and claims, unless otherwise stated,
the meaning of "about" should be assumed to be within an acceptable
error range for that particular value.
[0061] In one aspect of the present invention the immunomodulator
comprises a whole cell, non-pathogenic heat-killed Mycobacterium.
Examples of mycobacterial species for use in the present invention
include M. vaccae, M. thermoresistibile, M. flavescens, M. duvalii,
M. phlei, M. obuense, M. parafortuitum, M. sphagni, M. aichiense,
M. rhodesiae, M. neoaurum, M. chubuense, M. tokaiense, M.
komossense, M. aurum, M. w, M. tuberculosis, M. microti; M.
africanum; M. kansasii, M. marinum; M. simiae; M. gastri; M.
nonchromogenicum; M. terrae; M. triviale; M. gordonae; M.
scrofulaceum; M. paraffinicum; M. intracellulare; M. avium; M.
xenopi; M. ulcerans; M. diernhoferi, M. smegmatis; M. thamnopheos;
M. flavescens; M. fortuitum; M. peregrinum; M. chelonei; M.
paratuberculosis; M. leprae; M. lepraemurium and combinations
thereof.
[0062] The whole cell non-pathogenic heat-killed Mycobacterium is
preferably selected from M. vaccae, M. obuense, M. parafortuitum,
M. aurum, M. indicus pranii, M. phlei and combinations thereof.
More preferably the whole cell, non-pathogenic heat-killed
Mycobacterium is a rough variant. The amount of Mycobacterium
administered to the patient is sufficient to elicit a protective
immune response in the patient such that the patient's immune
system is able to mount an effective immune response to the cancer
or tumour. In certain embodiments of the invention, there is
provided a containment means comprising the effective amount of
heat-killed Mycobacterium for use in the present invention, which
typically may be from 10.sup.3 to 10.sup.11 organisms, preferably
from 10.sup.4 to 10.sup.10 organisms, more preferably from 10.sup.6
to 10.sup.10 organisms, and even more preferably from 10.sup.6 to
10.sup.9 organisms. The effective amount of heat-killed
Mycobacterium for use in the present invention may be from 10.sup.3
to 10.sup.11 organisms, preferably from 10.sup.4 to 10.sup.10
organisms, more preferably from 10.sup.6 to 10.sup.10 organisms,
and even more preferably from 10.sup.6 to 10.sup.9 organisms. Most
preferably the amount of heat-killed Mycobacterium for use in the
present invention is from 10.sup.7 to 10.sup.9 cells or organisms.
Typically, the composition according to the present invention may
be administered at a dose of from 10.sup.8 to 10.sup.9 cells for
human and animal use. Alternatively the dose is from 0.01 mg to 1
mg or 0.1 mg to 1 mg organisms presented as either a suspension or
dry preparation.
[0063] M. vaccae and M. obuense are particularly preferred.
[0064] M. vaccae and M. obuense induce a complex immune response in
the host. Treatment with these preparations will stimulate innate
and type-1 immunity, including Th1 and macrophage activation and
cytotoxic cell activity. They also independently down-regulate
inappropriate Th2 responses via immunoregulatory mechanisms. This
restores the healthy balance of the immune system.
[0065] The present invention may be used to treat a neoplastic
disease, such as solid or non-solid cancers. As used herein,
"treatment" encompasses the prevention, reduction, control and/or
inhibition of a neoplastic disease. Such diseases include a
sarcoma, carcinoma, adenocarcinoma, melanoma, myeloma, blastoma,
glioma, lymphoma or leukemia. Exemplary cancers include, for
example, carcinoma, sarcoma, adenocarcinoma, melanoma, neural
(blastoma, glioma), mesothelioma and reticuloendothelial, lymphatic
or haematopoietic neoplastic disorders (e.g., myeloma, lymphoma or
leukemia). In particular aspects, a neoplasm, tumour or cancer
includes a lung adenocarcinoma, lung carcinoma, diffuse or
interstitial gastric carcinoma, colon adenocarcinoma, prostate
adenocarcinoma, esophagus carcinoma, breast carcinoma, pancreas
adenocarcinoma, ovarian adenocarcinoma, adenocarcinoma of the
adrenal gland, adenocarcinoma of the endometrium or uterine
adenocarcinoma.
[0066] Neoplasia, tumours and cancers include benign, malignant,
metastatic and non-metastatic types, and include any stage (I, II,
III, IV or V) or grade (G1, G2, G3, etc.) of neoplasia, tumour, or
cancer, or a neoplasia, tumour, cancer or metastasis that is
progressing, worsening, stabilized or in remission. Cancers that
may be treated according to the invention include but are not
limited to: bladder, blood, bone, bone marrow, brain, breast,
colon, esophagus, gastrointestines, gum, head, kidney, liver, lung,
nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue,
or uterus. Preferably, the cancer is selected from prostate cancer,
liver cancer, renal cancer, lung cancer, breast cancer, colorectal
cancer, pancreatic cancer, brain cancer, hepatocellular cancer,
lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian
cancer, thyroid cancer, melanoma, head and neck cancer, skin cancer
and soft tissue sarcoma and/or other forms of carcinoma. The tumour
may be metastatic or a malignant tumour.
[0067] More preferably, the cancer is pancreatic, colorectal,
prostate, ovarian or prostate cancer a.
[0068] In an embodiment of the invention, the checkpoint inhibitor
therapy comprising administration of a blocking agent, selected
from a cell, protein, peptide, antibody or antigen binding fragment
thereof, directed against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3,
B7-H4, B7-H6, A2AR, or IDO, and combinations thereof, in
combination with a whole cell, non-pathogenic heat-killed
Mycobacterium, is used to reduce or inhibit metastasis of a primary
tumour or cancer to other sites, or the formation or establishment
of metastatic tumours or cancers at other sites distal from the
primary tumour or cancer thereby inhibiting or reducing tumour or
cancer relapse or tumour or cancer progression. Preferably, the
blocking agent is directed against CTLA-4, PD-1, or PD-L1, and
combinations thereof. Most preferably, the blocking agent is
directed against PD-L1.
[0069] In a further embodiment of the invention, there is provided
a combination therapy for treating cancer, comprising an
immunomodulator and checkpoint inhibitor(s), wherein said
checkpoint inhibition therapy comprises administration of a
blocking agent, selected from a cell, protein, peptide, antibody or
antigen binding fragment thereof, directed against CTLA-4, PD-1,
PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or IDO, and
combinations thereof, wherein the immunomodulator comprises a whole
cell, non-pathogenic heat-killed Mycobacterium, with the potential
to elicit potent and durable immune responses with enhanced
therapeutic benefit and more manageable toxicity. Preferably, the
blocking agent is directed against CTLA-4, PD-1, or PD-L1, and
combinations thereof. Most preferably, the blocking agent is
directed against PD-L1.
[0070] In a further embodiment of the invention, there is provided
a combination therapy for treating cancer, comprising an
immunomodulator which; (i) stimulates innate and type-1 immunity,
including Th1 and macrophage activation and cytotoxic cell
activity, and, (ii) independently down-regulates inappropriate Th2
responses via immunoregulatory mechanisms; and, a checkpoint
inhibitor, optionally wherein the immunomodulator is a whole cell
non-pathogenic, heat-killed Mycobacterium selected from M. vaccae
or M. obuense.
[0071] In an embodiment of the invention is provided a method for
treating cancer and/or preventing the establishment of metastases
by employing a checkpoint inhibitor selected from a cell, protein,
peptide, antibody or antigen binding fragment thereof, directed
against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6,
A2AR, or IDO, and combinations thereof, which act synergistically
with a whole cell non-pathogenic, heat-killed Mycobacterium.
Preferably, the checkpoint inhibitor employed is directed against
CTLA-4, PD-1, or PD-L1, and combinations thereof. Most preferably,
the blocking agent is directed against PD-L1.
[0072] In further embodiments, methods of the invention include,
one or more of the following: 1) reducing or inhibiting growth,
proliferation, mobility or invasiveness of tumour or cancer cells
that potentially or do develop metastases, 2) reducing or
inhibiting formation or establishment of metastases arising from a
primary tumour or cancer to one or more other sites, locations or
regions distinct from the primary tumour or cancer; 3) reducing or
inhibiting growth or proliferation of a metastasis at one or more
other sites, locations or regions distinct from the primary tumour
or cancer after a metastasis has formed or has been established, 4)
reducing or inhibiting formation or establishment of additional
metastasis after the metastasis has been formed or established, 5)
prolonged overall survival, 6) prolonged progression free survival,
or 7) disease stabilisation.
[0073] In an embodiment of the invention, administration of the
checkpoint inhibitor, selected from a cell, protein, peptide,
antibody or antigen binding fragment thereof, directed against
CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or
IDO, and combinations thereof, in combination therapy with a whole
cell, heat-killed non-pathogenic Mycobacterium, provides a
detectable or measurable improvement in a condition of a given
subject, such as alleviating or ameliorating one or more adverse
(physical) symptoms or consequences associated with the presence of
a cell proliferative or cellular hyperproliferative disorder,
neoplasia, tumour or cancer, or metastasis, i e., a therapeutic
benefit or a beneficial effect.
[0074] Preferably, the blocking agent is directed against CTLA-4,
PD-1, or PD-L1, and combinations thereof. Most preferably, the
blocking agent is directed against PD-L1.
[0075] A therapeutic benefit or beneficial effect is any objective
or subjective, transient, temporary, or long-term improvement in
the condition or pathology, or a reduction in onset, severity,
duration or frequency of an adverse symptom associated with or
caused by cell proliferation or a cellular hyperproliferative
disorder such as a neoplasia, tumour or cancer, or metastasis. It
may lead to improved survival. A satisfactory clinical endpoint of
a treatment method in accordance with the invention is achieved,
for example, when there is an incremental or a partial reduction in
severity, duration or frequency of one or more associated
pathologies, adverse symptoms or complications, or inhibition or
reversal of one or more of the physiological, biochemical or
cellular manifestations or characteristics of cell proliferation or
a cellular hyperproliferative disorder such as a neoplasia, tumour
or cancer, or metastasis. A therapeutic benefit or improvement
therefore may be, but is not limited to destruction of target
proliferating cells (e.g., neoplasia, tumour or cancer, or
metastasis) or ablation of one or more, most or all pathologies,
adverse symptoms or complications associated with or caused by cell
proliferation or the cellular hyperproliferative disorder such as a
neoplasia, tumour or cancer, or metastasis. However, a therapeutic
benefit or improvement need not be a cure or complete destruction
of all target proliferating cells (e.g., neoplasia, tumour or
cancer, or metastasis) or ablation of all pathologies, adverse
symptoms or complications associated with or caused by cell
proliferation or the cellular hyperproliferative disorder such as a
neoplasia, tumour or cancer, or metastasis. For example, partial
destruction of a tumour or cancer cell mass, or a stabilization of
the tumour or cancer mass, size or cell numbers by inhibiting
progression or worsening of the tumour or cancer, can reduce
mortality and prolong lifespan even if only for a few days, weeks
or months, even though a portion or the bulk of the tumour or
cancer mass, size or cells remain.
[0076] Specific non-limiting examples of therapeutic benefit
include a reduction in neoplasia, tumour or cancer, or metastasis
volume (size or cell mass) or numbers of cells, inhibiting or
preventing an increase in neoplasia, tumour or cancer volume (e.g.,
stabilizing), slowing or inhibiting neoplasia, tumour or cancer
progression, worsening or metastasis, or inhibiting neoplasia,
tumour or cancer proliferation, growth or metastasis.
[0077] In an embodiment of the invention, administration of the
checkpoint inhibitor, selected from a cell, protein, peptide,
antibody or antigen binding fragment thereof, directed against
CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or
IDO, and combinations thereof, in combination therapy with the
whole cell, non-pathogenic heat-killed Mycobacterium, provides a
detectable or measurable improvement or overall response according
to the irRC (as derived from time-point response assessments and
based on tumour burden), including one of more of the following:
(i) irCR - complete disappearance of all lesions, whether
measurable or not, and no new lesions (confirmation by a repeat,
consecutive assessment no less than 4 weeks from the date first
documented), (ii) irPR--decrease in tumour burden 50% relative to
baseline (confirmed by a consecutive assessment at least 4 weeks
after first documentation). Preferably, the checkpoint inhibitor
employed is directed against CTLA-4, PD-1, or PD-L1, and
combinations thereof.
[0078] An invention method may not take effect immediately. For
example, treatment may be followed by an increase in the neoplasia,
tumour or cancer cell numbers or mass, but over time eventual
stabilization or reduction in tumour cell mass, size or numbers of
cells in a given subject may subsequently occur.
[0079] Additional adverse symptoms and complications associated
with neoplasia, tumour, cancer and metastasis that can be
inhibited, reduced, decreased, delayed or prevented include, for
example, nausea, lack of appetite, lethargy, pain and discomfort.
Thus, a partial or complete decrease or reduction in the severity,
duration or frequency of an adverse symptom or complication
associated with or caused by a cellular hyperproliferative
disorder, an improvement in the subjects quality of life and/or
well-being, such as increased energy, appetite, psychological
well-being, are all particular non-limiting examples of therapeutic
benefit.
[0080] A therapeutic benefit or improvement therefore can also
include a subjective improvement in the quality of life of a
treated subject. In an additional embodiment, a method prolongs or
extends lifespan (survival) of the subject. In a further
embodiment, a method improves the quality of life of the
subject.
[0081] In a most preferred embodiment, administration of the
checkpoint inhibitor, selected from a cell, protein, peptide,
antibody or antigen binding fragment thereof, directed against
CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or
IDO, and combinations thereof, in combination therapy with a whole
cell, non-pathogenic heat-killed Mycobacterium results in a
clinically relevant improvement in one or more markers of disease
status and progression selected from one or more of the following:
(i): overall survival, (ii): progression-free survival, (iii):
overall response rate, (iv): reduction in metastatic disease, (v):
circulating levels of tumour antigens such as carbohydrate antigen
19.9 (CA19.9) and carcinembryonic antigen (CEA) or others depending
on tumour, (vii) nutritional status (weight, appetite, serum
albumin), (viii): pain control or analgesic use, (ix): CRP/albumin
ratio. Preferably, the checkpoint inhibitor adminstered is directed
against CTLA-4, PD-1, or PD-L1, and combinations thereof.
[0082] Treatment with non-pathogenic, heat-killed whole cell M.
vaccae and M. obuense gives rise to more complex immunity including
not only the development of innate immunity and type-1 immunity,
but also immunoregulation which more efficiently restores
appropriate immune functions.
[0083] In another preferred embodiment, the checkpoint inhibition
therapy comprises administration of a sub-therapeutic amount and/or
duration of a blocking agent, selected from a cell, protein,
peptide, antibody or antigen binding fragment thereof, directed
against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6,
A2AR, or IDO, and combinations thereof. Preferably, the checkpoint
inhibition therapy comprises administration of a sub-therapeutic
amount of a blocking agent directed against CTLA-4, PD-1, or PD-L1,
and combinations thereof.
[0084] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, selected from
a cell, protein, peptide, antibody or antigen binding fragment
thereof, directed against PD-1 and/or, PD-L1.
[0085] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, selected from
a cell, protein, peptide, antibody or antigen binding fragment
thereof, directed against PD-1 and/or, PD-L1, simultaneously,
separately or sequentially with administration of a blocking
antibody or antigen binding fragment thereof, directed against
CTLA-4.
[0086] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, wherein said
blocking agent is an antibody selected from the group consisting
of: ipilimumab, nivolumab, pembrolizumab, atezolizumab,
tremelimumab (as described in WO2006/101692), MEDI-0680 (Astra
Zeneca), MDX-1105 (Medarex), MEDI-4736 (Medimmune, Inc.) or
MSB001078C (Merck KGaA), and combinations thereof.
[0087] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, wherein said
blocking agent is an antibody selected from ipilimumab, nivolumab,
pembrolizumab, atezolizumab, tremelimumab, and combinations
thereof.
[0088] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent wherein said
blocking agent is pembrolizumab (as described in WO2012/135408),
and wherein said patient has mismatch-repair deficient tumours
associated with said cancer and/or exhibits PD-L1 expression in at
least 10%, or 20%, or 30%, or 40%, or 50% or more of tumour cells,
as measured using the SP142 immunohistochemistry antibody assay
[0089] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, wherein said
blocking agent is ipilimumab (as described in U.S. Pat. Nos.
9,868,388, 8,962,804 and 8,809,562) and administered intravenously
at a dose of 2 mg/mg or less every three weeks, optionally for a
maximum of four infusions.
[0090] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, wherein said
blocking agent is nivolumab (Humab ref: 5C4 as described in U.S.
Pat. No. 8,004,449) and administered intravenously at a dose of at
least 3, or 5 or 10 mg/mg or more every four weeks, optionally
wherein said patient exhibits PD-L1 expression in at least 1%, 5%
or 10% or more of tumour cells, as measured using the SP142
immunohistochemistry antibody assay.
[0091] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent wherein said
blocking agent is atezolizumab (sequence 21 from U.S. Pat. No.
8,217,149) and administered intravenously at a dose of at least 10
or 15 mg/kg or more every three weeks, optionally wherein said
patient exhibits PD-L1 expression in at least 1%, 5% or 10% or more
of tumour cells and/or tumour-infiltrating immune cells selected
from B-cells and NK cells, as measured using the SP142
immunohistochemistry antibody assay.
[0092] In another preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, selected from
a cell, protein, peptide, antibody or antigen binding fragment
thereof, directed against PD-L2.
[0093] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, selected from
a cell, protein, peptide, antibody or antigen binding fragment
thereof, directed against, PD-L2, simultaneously, separately or
sequentially with administration of a blocking antibody or antigen
binding fragment thereof, directed against CTLA-4.
[0094] In a further preferred embodiment, the checkpoint inhibition
therapy comprises administration of a blocking agent, wherein said
blocking agent is an antibody selected from the group consisting
of: AMP-224 (Amplimmune, Inc), BMS-986016 or MGA-271, and
combinations thereof.
[0095] AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble
receptor described in 102010/027827 and WO2011/066342,
[0096] BMS-986016 is a fully human antibody specific for human
LAG-3 that was isolated from immunized transgenic mice expressing
human immunoglobulin genes. It is expressed as an IgG4 isotype
antibody that includes a stabilizing hinge mutation (S228P) for
attenuated Fc receptor binding in order to reduce or eliminate the
possibility of antibody- or complement- mediated target cell
killing. The heavy and light chain amino acid sequences of
BMS-986016 are provided in SEQ ID NOs: 17 and 18 of
WO2015/042246.
[0097] In another embodiment, the checkpoint inhibition therapy
comprises administration of BMS-986016 administered intravenously
at a dose of between about 20 mg and about 8000 mg, every two
weeks, optionally for a maximum of forty eight infusions.
[0098] In a further embodiment, the checkpoint inhibition therapy
comprises administration of a blocking agent wherein said blocking
agent is an antibody that specifically binds to B7-H3 such as
MGA271 (an a-B7-H3 humanized monoclonal antibody, Macrogenics,
Inc.) or other antibodies as described in US Application
Publication Number 2012-0294796, the contents of which are
incorporated herein by reference; or indoleamine-2,3-dioxygenase
(IDO) inhibitors such as D-1 -methyl -tryptophan (Lunate) and other
compounds described in U.S. Pat. No. 7,799,776, the contents of
which are incorporated herein by reference
[0099] The term "combination" as used throughout the specification,
is meant to encompass the administration of the checkpoint
inhibitor simultaneously, separately or sequentially with
administration of the whole cell, non-pathogenic heat-killed
Mycobacterium. Accordingly, the checkpoint inhibitor and the whole
cell, non-pathogenic heat-killed Mycobacterium may be present in
the same or separate pharmaceutical formulations, and administered
at the same time or at different times.
[0100] Thus, a whole cell, non-pathogenic heat-killed Mycobacterium
and the checkpoint inhibitor may be provided as separate
medicaments for administration at the same time or at different
times.
[0101] Preferably, a whole cell, non-pathogenic heat-killed
Mycobacterium and checkpoint inhibitor are provided as separate
medicaments for administration at different times. When
administered separately and at different times, either the whole
cell, non-pathogenic heat-killed Mycobacterium or checkpoint
inhibitor may be administered first; however, it is suitable to
administer checkpoint inhibitor followed by the whole cell,
non-pathogenic heat-killed Mycobacterium. In addition, both can be
administered on the same day or at different days, and they can be
administered using the same schedule or at different schedules
during the treatment cycle.
[0102] In an embodiment of the invention, a treatment cycle
consists of the administration of a whole cell, non-pathogenic
heat-killed Mycobacterium daily, weekly fortnightly or monthly,
simultaneously with checkpoint inhibitor weekly. Alternatively, the
whole cell, non-pathogenic heat-killed Mycobacterium is
administered before and/or after the administration of the
checkpoint inhibitor.
[0103] In another embodiment of the invention, the whole cell,
non-pathogenic heat-killed Mycobacterium is administered to the
patient before and after administration of a checkpoint inhibitor.
That is, in one embodiment, the whole cell, non-pathogenic
heat-killed Mycobacterium is administered to the patient before and
after said checkpoint inhibitor.
[0104] Dose delays and/or dose reductions and schedule adjustments
are performed as needed depending on individual patient tolerance
to treatments.
[0105] Alternatively, the administration of checkpoint inhibitor
may be performed simultaneously with the administration of the
effective amounts of the whole cell, non-pathogenic heat-killed
Mycobacterium.
[0106] The whole cell, non-pathogenic heat-killed Mycobacterium,
may be administered to the patient via the parenteral, oral,
sublingual, nasal or pulmonary route. In a preferred embodiment,
the immunomodulator is administered via a parenteral route selected
from subcutaneous, intradermal, subdermal, intraperitoneal,
intravenous and intravesicular injection. Alternatively,
administration by the parenteral route may comprise intratumoural
injection of said non-pathogenic heat-killed Mycobacterium and/or
blocking agent
[0107] The subject whom is to undergo checkpoint inhibition therapy
according to the present invention may do so simultaneously,
separately or sequentially with administration of the whole cell,
non-pathogenic heat-killed Mycobacterium.
[0108] In an aspect of the invention, the effective amount of the
whole cell, non-pathogenic heat-killed Mycobacterium may be
administered as a single dose. Alternatively, the effective amount
of the whole cell, non-pathogenic heat-killed Mycobacterium may be
administered in multiple (repeat) doses, for example two or more,
three or more, four or more, five or more, ten or more, or twenty
or more repeat doses. The whole cell non-pathogenic heat-killed
Mycobacterium may be administered between about 4 weeks and about 1
day prior to checkpoint inhibition therapy, such as between about 4
weeks and 1 week, or about between 3 weeks and 1 week, or about
between 3 weeks and 2 weeks. Administration may be presented in
single or multiple doses.
[0109] In a preferred embodiment of the invention there is a whole
cell, non-pathogenic heat-killed Mycobacterium. for use in the
treatment of neoplastic disease in combination with a checkpoint
inhibitor, selected from a cell, protein, peptide, antibody or
antigen binding fragment thereof, directed against CTLA-4, PD-1,
PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6, A2AR, or IDO, and
combinations thereof, wherein said Mycobacterium is administered to
the subject before, concurrently with and/or after the checkpoint
inhibitor is administered. Preferably, the Mycobacterium is for use
in treatment of a neoplastic disease in combination with checkpoint
inhibitors directed against PD-1, PD-L1, or CTLA-4, and
combinations thereof.
[0110] In another preferred embodiment of the invention is a method
of treating, reducing, inhibiting or controlling a neoplasia,
tumour or cancer in a subject, wherein said method comprises
simultaneously, separately or sequentially administering to the
subject, (i) a checkpoint inhibitor, selected from a cell, protein,
peptide, antibody or antigen binding fragment thereof, directed
against CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, B7-H3, B7-H4, B7-H6,
A2AR, or IDO, and combinations thereof, and (ii) an
immunomodulator, wherein said method results in enhanced
therapeutic efficacy relative to administration of the checkpoint
inhibitor or immunomodulator alone, and wherein the immunomodulator
comprises a whole cell, non-pathogenic heat-killed Mycobacterium,
and optionally wherein said method comprises administration of a
sub-therapeutic amount of said checkpoint inhibitor.
[0111] Preferably, the checkpoint inhibitor is directed against
CTLA-4, PD-1, or PD-L1, and combinations thereof. Most preferably,
the blocking agent is directed against PD-L1.
[0112] In another preferred embodiment of the invention is a method
of treating, reducing, inhibiting or controlling a neoplasia,
tumour or cancer in a subject, wherein said method comprises
simultaneously, separately or sequentially administering to the
subject, (i) a checkpoint inhibitor, and (ii) an immunomodulator,
preferably a whole cell heat-killed Mycobacterium, wherein said
checkpoint inhibition therapy comprises administration of a
blocking agent, selected from a cell, protein, peptide, antibody or
antigen binding fragment thereof, directed against PD-1 and/or
PD-L1.
[0113] In yet another preferred embodiment of the invention is a
method of treating, reducing, inhibiting or controlling a
neoplasia, tumour or cancer in a subject, wherein said method
comprises simultaneously, separately or sequentially administering
to the subject, (i) a checkpoint inhibitor, and (ii) a whole cell,
non-pathogenic heat-killed Mycobacterium, wherein said checkpoint
inhibition therapy comprises administration of a blocking agent,
selected from an antibody or antigen binding fragment thereof,
directed against CTLA-4, PD-1 or PD-L1, and combinations thereof,
wherein said checkpoint inhibition therapy comprises administration
of a sub-therapeutic amount and/or duration of said blocking
antibody or antigen binding fragment thereof.
[0114] In yet another embodiment of the invention is a method of
treating, reducing, inhibiting or controlling a neoplasia, tumour
or cancer in a subject, wherein said method comprises
simultaneously, separately or sequentially administering to the
subject, (i) two or more checkpoint inhibitors, and (ii) a whole
cell, non-pathogenic heat-killed Mycobacterium, wherein said
checkpoint inhibition therapy comprises administration of two or
more blocking agent, selected from a cell, protein, peptide,
antibody or antigen binding fragment thereof, directed against
CTLA-4, PD-1 or PD-L1, and combinations thereof, wherein said
checkpoint inhibition therapy optionally comprises administration
of a sub-therapeutic amount and/or duration of either blocking
agent.
[0115] In one embodiment of the present invention, the whole cell,
non-pathogenic heat-killed Mycobacterium may be in the form of a
medicament administered to the patient in a dosage form.
[0116] A container according to the invention in certain instances
may be a vial, an ampoule, a syringe, capsule, tablet or a tube. In
some cases, the mycobacteria may be lyophilized and formulated for
resuspension prior to administration. However, in other cases, the
mycobacteria are suspended in a volume of a pharmaceutically
acceptable liquid. In some of the most preferred embodiments there
is provided a container comprising a single unit dose of
mycobacteria suspended in pharmaceutically acceptable carrier
wherein the unit dose comprises about 1.times.10.sup.6 to about
1.times.10.sup.10 organisms. In some very specific embodiments the
liquid comprising suspended mycobacteria is provided in a volume of
between about 0.1 ml and 10 ml, or between about 0.3 ml and 2 ml or
between about 0.5 ml and 2 ml. The foregoing compositions provide
ideal units for immunotherapeutic applications described
herein.
[0117] Embodiments discussed in the context of a methods and/or
composition of the invention may be employed with respect to any
other method or composition described herein. Thus, an embodiment
pertaining to one method or composition may be applied to other
methods and compositions of the invention as well.
[0118] In some cases, whole cell non-pathogenic heat-killed
Mycobacteria are administered to specific sites on or in a subject.
For example, the mycobacterial compositions according to the
invention, such as those comprising M. obuense in particular, may
be administered adjacent to tumours or adjacent to lymph nodes,
such as those that drain tissue surrounding a tumour. Thus, in
certain instances sites administration of mycobacterial composition
may be near the posterior cervical, tonsillar, axillary, inguinal,
anterior cervical, sub-mandibular, sub mental or superclavicular
lymph nodes.
[0119] The whole cell, non-pathogenic heat-killed Mycobacterium may
be administered for the length of time the cancer or tumour(s) is
present in a patient or until such time the cancer has regressed or
stabilized. The whole cell, non-pathogenic heat-killed
Mycobacterium r may also be continued to be administered to the
patients once the cancer or tumour has regressed or stabilised.
[0120] Mycobacterial compositions according to the invention will
comprise an effective amount of mycobacteria typically dispersed in
a pharmaceutically acceptable carrier. The phrases
"pharmaceutically or pharmacologically acceptable" refers to
molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an animal,
such as, for example, a human, as appropriate. The preparation of
an pharmaceutical composition that contains mycobacteria will be
known to those of skill in the art in light of the present
disclosure, as exemplified by Remington's Pharmaceutical Sciences,
18th Ed. Mack Printing Company, 1990, Moreover, for animal (e.g.,
human) administration, it will be understood that preparations
should meet sterility, pyrogenicity, general safety and purity
standards. A specific example of a pharmacologically acceptable
carrier as described herein is borate buffer or sterile saline
solution (0.9% NaCl).
[0121] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives {e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, gels,
binders, excipients, disintegration agents, lubricants, sweetening
agents, flavouring agents, dyes, such like materials and
combinations thereof, as would be known to one of ordinary skill in
the art (see, for example, Remington's Pharmaceutical Sciences,
18th Ed. Mack Printing Company, 1990, pp. 1289-1329).
[0122] In a preferred embodiment, the whole cell, non-pathogenic
heat-killed Mycobacterium is administered via a parenteral route
selected from subcutaneous, intradermal, subdermal,
intraperitoneal, intravenous and intravesicular injection.
Intradermal injection enables delivery of an entire proportion of
the mycobacterial composition to a layer of the dermis that is
accessible to immune surveillance and thus capable of electing an
anti-cancer immune response and promoting immune cell proliferation
at local lymph nodes.
[0123] Though in highly preferred embodiments of the invention
mycobacterial compositions are administered by direct intradermal
injection, it is also contemplated that other methods of
administration may be used in some case. Thus in certain instances,
the whole cell, non-pathogenic heat-killed Mycobacterium of the
present invention can be administered by injection, infusion,
continuous infusion, intravenously, intradermally, intraarterially,
intraperitoneally, intralesionally, intravitreally, intravaginally,
intrarectally, topically, intratumourally, intramuscularly,
intraperitoneally, subcutaneously, subconjunctival,
intravesicularlly, mucosally, intrapericardially, intraumbilically,
intraocularally, orally, intracranially, intraarticularly,
intraprostaticaly, intrapleurally, intratracheally, intranasally,
topically, locally, inhalation (e.g. aerosol inhalation), via a
catheter, via a lavage, or by other method or any combination of
the forgoing as would be known to one of ordinary skill in the art
(see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990).
[0124] All publications mentioned in the above specification are
herein incorporated by reference. Various modifications and
variations of the described methods and system of the present
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the present invention.
Although the present invention has been described in connection
with specific preferred embodiments, it should be understood that
the invention as claimed should not be unduly limited to such
specific embodiments. Indeed, various modifications of the
described modes for carrying out the invention which are obvious to
those skilled in biochemistry and immunology or related fields are
intended to be within the scope of the following claims.
[0125] The invention is further described with reference to the
following non-limiting Example.
EXAMPLE 1
[0126] Adult C57BL/6 mice were injected subcutaneously on the flank
with 10.sup.5 cells from a pancreatic cancer cell line obtained
from KPC mice (Hingorani et al. Cancer Cell, 2005, 7:469-48). These
murine pancreatic cancer cells bear mutations in Kras, p53 and
Pdx-Cre (Hingorani et al. Cancer Cell, 2005, 7:469-48).
[0127] When the injected tumour cells had grown to become a
palpable tumour (day 0), mice were left untreated or received
treatment with: [0128] 1) 0.1 mg M. obuense NTCT 13365/mouse,
subcutaneously alternating injections in the scruff of the neck
with those at the base of the tail on alternating days over 5 day
period with a 2 day break for the length of the study; [0129] 2) 10
mg/kg anti-PDL-1 mAb or 10 mg/kg anti PD-1 mAb intraperitoneally
once weekly; [0130] 3) the combination of anti-PDL-1 or 10 mg/kg
anti PD-1 mAb and M. obuense NTCT 13365 at a dose and schedule
described above for the two compounds used singly.
[0131] Tumour growth was monitored over the course of the study to
determine whether the treatment administered had an effect on
reducing tumour size and improving prospects of survival.
[0132] Data presented in FIG. 1 show that mice which received the
treatment combination of anti-PDL-1 and M. obuense NTCT 13365
demonstrated a continued reduction in tumour size and appeared to
control the tumour. This reduction in tumour size was more
pronounced compared to mice receiving either treatment alone. Mice
left untreated had uncontrolled tumour growth and soon succumbed to
the disease.
EXAMPLE 2
[0133] The effects of combination treatment with IMM-101 and
checkpoint inhibitors were investigated in C57BL/6 mice bearing
subcutaneous B16-F10 tumours. The mice were engrafted at D0. Mice
were randomized on D1 and received a total of 8 SC injections of
IMM-101 at 0.1 mg/mouse on D1, D3, D5, D7, D9, D11, D13 and D15
(half of surviving mice) or D16 (half of surviving mice) (Q2Dx8) or
a total of 4 IP injections of anti-PD1 or anti-CTLA4 at 10 mg/kg
(twice weekly for two consecutive weeks on D1, D5, D8 and D12:
TWx2) alone or in combination. At Day 15 and 16, half of all
surviving mice were terminated after the last treatment. The tumour
immune infiltrate cells and spleen immune cells (the ratio of
CD3+CD8+ cells and FoxP3 Treg cells) characterization were
quantified by FACS analysis (FIG. 3).
* * * * *