Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMBINATION THERAPY FOR TREATING DISEASE
(Atty Docket Number ALT-013PC)
BACKGROUND OF THE INVENTION
Field of the invention
The invention relates to immunology. More particularly the invention relates
to the use of immunotherapy in combination with chemotherapy.
Summary of the Related Art
Despite the progress that modern medicine has made in treating cancer, cancer
recurrence remains a concern. For a majority of cancers, typical treatment
includes
surgery followed by high doses of chemotherapy. A majority of these patients
relapse
and do not respond to other chemotherapeutic treatments. These patients then
avail
themselves to experimental or salvage treatments.
Current experimental regimens focus on mixing chemotherapies in an attempt
to overcome resistance issues. Most of these treatments result in serious
blood
toxicities such as neutropenia, and thrombocytopenia. Other serious and
frustrating
symptoms to the patient include hair loss and nausea. Researchers are now
looking at
ways to enhance the immune system through less toxic means while still
eliminating
the cancer.
Many have turned to the use of chemotherapy in conjunction with antibody
treatments. Many of these have also presented similar toxicities to the
chemotherapy.
Thus, there remains a need to identify new treatments that not only treat the
initial symptoms of a disease, but also alleviate and/or prevent recurrence of
those
symptoms.
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BRIEF SUMMARY OF THE INVENTION
In a first aspect the invention provides a method for treating cancer,
comprising concurrently administering xenotypic monoclonal antibody and a
chemotherapeutic drug to a patient suffering from cancer. Preferably the
patient is
human.
In a second aspect the invention provides a method for treating cancer,
comprising surgical removal of the cancer, concurrent administration of a
chemotherapeutic drug and a xenotypic monoclonal antibody in a dose equal to
or less
than 2mg.
In a third aspect, the invention provides a method for treating cancer,
comprising surgical removal removal of the cancer, administration of a
xenotypic
monoclonal antibody on weeks 1, 3, 5, 9, followed by concurrent administration
of a
chemotherapeutic drug and a xenotypic monoclonal antibody on week 12 in a dose
equal to or less than 2mg.
In a fourth aspect, the invention provides a method for inducing a host
immune response in a patient against a multi-epitopic in vivo tumor antigen,
which
antigen does not elicit an effective host immune response, comprising
concurrently
administering to the patient a chemotherapeutic drug and a composition
comprising a
binding agent that specifically binds to a first epitope on the antigen and
allowing the
binding agent to form a binding agent/antigen pair, wherein a host immune
response
is elicited against a second epitope on the antigen.
In a fifth aspect, the invention provides a method for treating cancer,
comprising concurrent administration of a chemotherapeutic drug, a binding
agent,
and an antigen.
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In a sixth aspect, the invention provides method for inducing a host immune
response in a patient against a multi-epitopic in vivo tumor antigen, which
antigen
does not elicit an effective host immune response, comprising concurrently
administering to the patient a chemotherapeutic drug and a composition
comprising a
binding agent present in an amount of from 0.1 g to 2mg per kg of body weight
of
the host, and wherein the binding agent specifically binds to an epitope on
the antigen
and an effective host immune response is elicited against a second epitope on
the
antigen.
In a further aspect, the invention provides a use of a xenotypic monoclonal
antibody or a fragment thereof and a chemotherapeutic drug for the manufacture
of a
medicament or medicaments for treating cancer, wherein the antibody or
fragment
thereof binds to a tumor antigen and elicits an effective T cell or humoral
immune
response against the antigen in a patient, wherein the antibody and
chemotherapeutic
drug are to be concurrently administered, and wherein the antibody or fragment
thereof is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4,
Alt-5, and
Alt-6 or a fragment thereof, wherein the tumor antigen is selected from the
group
consisting of CA125, MUC-1, PSA, CA19.9, and TAG-72; and wherein the
chemotherapeutic drug is selected from the group consisting of carboplatin,
cisplatin,
docetaxel, paclitaxel, doxorubicin, HC1 liposome injection, topotecan,
hydrochloride,
gemcitabine, cyclophosphamide, etoposide, platinum, and any combination
thereof.
"Medicament" as used herein means a composition or agent for treating a
patient suffering from cancer.
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BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a table showing the results of three clinical studies where Alt-2
is
administered concurrently with a chemotherapeutic drug.
Figure 2 is a diagram showing a non-limiting embodiment of the invention.
Figure 3 is a graph showing the difference in the numbers between Ab2
responders
(white squares) (effective immune response) and Ab2 non-responders (black
squares)(
ineffective immune response) with time.
Figure 4 is a table showing the different disease characteristics of Ab2
responders and
Ab2 non-responders.
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DETAILED DESCRIPTION
The present invention stems from the discovery that a combination of
immunotherapy with traditional chemotherapy and/or radiotherapy alleviates
and/or
prevents the recurrence of cancer. The presence of a host anti-xenotypic
antibody
5 response in a patient will stimulate an immune response. The inventors have
exploited this discovery to develop therapeutics containing binding agents
useful in
immunotherapy and chemotherapeutic or radiotherapeutic drugs, as well as
methods
for using these therapeutics. The patents and publications cited herein
reflect the level
of skill in this field. In the case of any conflict between a cited reference
and this
specification, this specification shall prevail.
Accordingly in a first aspect the invention provides a method for treating
cancer, comprising concurrently administering xenotypic monoclonal antibody
and a
chemotherapeutic drug to a patient suffering from cancer. In some embodiments
of
the invention, the binding by the xenotypic monoclonal antibody of a first
single
epitope exposes a second distinct epitope on the antigen. In some embodiments
of the
invention, the xenotypic monoclonal antibody, when bound to the antigen, forms
an
immunogenic complex. Exemplary xenotypic monoclonal antibodies ("MAb"),
preferably include IgGl antibodies; chimeric monoclonal antibodies ("C-MAb");
humanized antibodies; genetically engineered monoclonal antibodies ("G-MAb");
fragments of monoclonal antibodies (including but not limited to "F(Ab)2",
"F(Ab)"
and "Dab"); and single chains representing the reactive portion of monoclonal
antibodies ("SC-MAb"). The binding agent may be labeled or unlabeled.
Where the patient is human, preferred xenotypic monoclonal antibodies
include, without limitation, murine monoclonal antibodies. Particularly
preferred
murine monoclonal antibodies include Alt-I (murine IgGI, specifically binds to
MUC-1; ATCC No. PTA-975; American Type Culture Collection, Manassas, VA),
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Alt-2 (OvaRex MAb B43.13, murine IgG 1, specifically binds to CAI 25; ATCC No.
PTA-1883), Alt3 (murine IgG3, specifically binds to CA19.9; ATCC No. PTA-
2691),
Alt-4 (murine IgM, specifically binds to CA19.9; ATCC No. PTA-2692), Alt-5
(murine IgGI, specifically binds to CAI9.9; ATCC No. PTA-2690); and Alt-6
(murine IgGI, specifically binds to prostate specific antigen (PSA); ATCC No.
HB-
12526).
The methods according to the invention are useful for providing a therapeutic
benefit to patients suffering from cancer. As used herein, the term "cancer"
is used to
mean a condition in which a cell in a patient's body undergoes abnormal,
uncontrolled
proliferation. The abnormal cell may proliferate to form a solid tumor, or may
proliferate to form a multitude of cells (e.g., leukemia). Note that because
cancer is
the abnormal, uncontrolled proliferation of a patient's cell, the term does
not
encompass the normal proliferation of a cell, such as a stem cell or a
spermatocyte.
By "treating a patient suffering from cancer" is meant that the patient's
symptoms are alleviated following treatment according to the invention. In one
non-
limiting example, a patient suffering from a highly metastatic cancer (e.g.,
breast
cancer) is treated where additional metastasis either do not occur, or are
reduced in
number as compared to a patient who does not receive treatment. In another non-
limiting example, a patient is treated where the patient's solid cancer either
becomes
reduced in size or does not increase in size as compared to a patient who does
not
receive treatment. In yet another non-limiting example, the number of cancer
cells
(e.g., leukemia cells) in a treated patient either does not increase or is
reduced as
compared to the number of cancer cells in a patient who does not receive
treatment.
In preferred embodiments the patient is human.
It will be appreciated that a "patient suffering from cancer" of the invention
may express the mutant protein and not yet be symptomatic for the disease. For
example, where the cancer is colon cancer (which is associated with the mutant
K-ras
protein), a patient with a mutant K-ras protein in some cells of the colon is
a patient
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according to the invention even though that patient may not yet be symptomatic
for
colon cancer. "Associated with a mutant protein" means signs or symptoms of
illness
in a majority of patients are present when the mutant protein is present in
the patient's
body, but in which signs or symptoms of illness are absent when the mutant
protein is
absent from the patient's body. "Signs or symptoms of illness" are clinically
recognized manifestations or indications of disease.
Preferably, the therapeutic compositions of the invention further comprise a
pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier"
is
meant a carrier that is physiologically acceptable to the administered
patient. One
exemplary pharmaceutically acceptable carrier is physiological saline. Other
pharmaceutically-acceptable carriers and their formulations are well-known and
generally described in, for example, Remington's pharmaceutical Sciences (18`h
Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990)
"Administering" as used herein means providing the composition to the
patient in a manner that results in the composition being inside the patient's
body.
Such an administration can be by any route including, without limitation,
parenteral,
sub-cutaneous, intradermal, intravenous, intra-arterial, intraperitoneal, and
intramuscular.
In certain embodiments of the invention, the chemotherapeutic drug used is
commercially available. Some non limiting examples include carboplatin,
cisplatin,
docetaxel, paclitaxel, doxorubicin, HCI liposome injection, topotecan,
hydrochloride,
gemcitabine, cyclophosphamide, and etoposide or any combination thereof.
In preferred embodiments the chemotherapeutic drug is administered within a
week before or after the murine monoclonal antibody.
In a second aspect the invention provides a method for treating cancer,
comprising surgery, administration of a chemotherapeutic drug, administration
of a
xenotypic monoclonal antibody in a dose equal to or less than 2mg given by
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intravenous infusion over 20 minutes during weeks 1, 3, 5, 9, then every 8
weeks,
followed by administration of a chemotherapeutic drug within 5 days of the
administration of the binding agent.
In certain, non-limiting embodiments of the invention, the xenotypic antibody,
e.g. Alt-2 is administered as a 2 mg dose dissolved in 50 mL saline and
infused slowly
preferably over approximately 20 minutes. If an allergic or other reaction
occurs that
may limit the completion of the dose, then a lower dose may be employed at
that time
or with subsequent treatments, so that the expected dose range would be 1-2 mg
per
treatment. Premedication with oral or intravenous dyphenhydramine 25 to 50 mg
is
usually administered to lessen the risk of allergic reaction to the protein.
The
schedule used for combined Alt-2 and chemotherapy comprises administering Alt-
2 at
the dose above at weeks 1, 3, 5, 7, 9 with chemotherapy administered with Alt-
2 on
weeks 12 through 26. Alt-2 may be started after recovery from any required
surgery
that is done prior to the chemotherapy, and then continued up to and during
the
chemotherapy treatment period. The chemotherapy can be given in 3-4 week
cycles
or other schedules according to the treating physician and common clinical
practice.
Chemotherapy may continue for up to six cycles followed by the xenotypic
antibody
administration every twelve weeks for up to two years.
In a third aspect the invention provides a method for treating cancer,
comprising surgery, followed within seven days by administration of a
xenotypic
monoclonal antibody in a dose equal to or less than 2mg given by intravenous
infusion over 20 minutes during weeks 1, 3, 5, 9, then every 8 weeks with
concurrent
administration of a chemotherapeutic drug on week 3 and thereafter.
In another non-limiting example the murine antibody is administered at week
1 after completing standard surgery but has not yet begun chemotherapy. The
murine
antibody is administered in a dose equal to or less than 2mg through a 20
minute
intravenous infusion followed by a second treatment and concurrent
administration of
a chemotherapeutic drug on weeks 6 and beyond. "Concurrent Administration"
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means administration within a relatively short time period from each other.
Preferably such time period is less than 2 weeks, more preferably less than 7
days,
most preferably less than 1 day and could even be administered simultaneously.
The expected progression-free survival times may be measured in months to
years, depending on prognostic factors including the number of relapses, stage
of
disease, and other factors. Overall survival is also measured in months to
years. In
the case of ovarian cancer, the addition of the xenotypic monoclonal antibody,
Alt-2
is expected to increase the time to recurrence or progression, and may also
prolong
the survival time. Any improvement of 2 months or longer is usually considered
to
be clinically meaningful.
In a fourth aspect, the invention provides a method for inducing a host
immune response in a patient against a multi-epitopic in vivo tumor antigen in
present
in the host serum, which antigen does not elicit a host immune response,
comprising
administering to the patient a chemotherapeutic drug and a composition
comprising a
binding agent that specifically binds to a first epitope on the antigen and
allowing the
binding agent to form a binding agent/antigen pair, wherein a host immune
response
is elicited against a second epitope on the antigen. Exemplary multi-epitopic
antigens
are described in Nicodemus C.F. et al, Expert Rev. Vaccines 1(1), 34-48
(2002), Qi et
al, Hybridoma and Hybridomics 20, 313-323 (2001), and Berlyn et al., Clin.
Immunol. 101, 276-283, (2001).
A "binding agent", as used herein, refers to one member of a binding pair,
including an immunologic pair, e.g., a binding moiety that is capable of
binding to an
antigen, preferably a single epitope expressed on the antigen, such as a pre-
determined tumor antigen. In some embodiments of the invention, the binding of
a
first single epitope exposes a second distinct epitope on the antigen. In some
embodiments of the invention, the binding agent, when bound to the antigen,
forms an
immunogenic complex. Exemplary binding agents include, but are not limited to:
antibodies, monoclonal antibodies ("MAb"), preferably IgGI antibodies;
chimeric
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monoclonal antibodies ("C-MAb"); humanized antibodies; genetically engineered
monoclonal antibodies ("G-MAb"); fragments of monoclonal antibodies (including
but not limited to "F(Ab)2", "F(Ab)" and "Dab"); single chains representing
the
reactive portion of monoclonal antibodies ("SC-MAb"); antigen-binding
peptides;
5 tumor-binding peptides; a protein, including receptor proteins; peptide;
polypeptide;
glycoprotein; lipoprotein, or the like, e.g., growth factors; lymphokines and
cytokines;
enzymes, immune modulators; hormones, for example, somatostatin; any of the
above
joined to a molecule that mediates an effector function; and mimics or
fragments of
any of the above. The binding agent may be labeled or unlabeled.
10 Preferred binding agents of the invention are monoclonal antibodies. Where
the patient is human, these xenotypic monoclonal antibodies include, without
limitation, murine monoclonal antibodies. Particularly preferred murine
monoclonal
antibodies include Alt-I (murine IgGI, specifically binds to MUC-1; ATCC No.
PTA-975; American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex MAb
B43.13, murine IgGI, specifically binds to CA125; ATCC No. PTA-1883), Alt3
(murine IgG3, specifically binds to CA19.9; ATCC No. PTA-2691), Alt-4 (murine
IgM, specifically binds to CA19.9; ATCC No. PTA-2692), Alt-5 (murine IgGI,
specifically binds to CA19.9; ATCC No. PTA-2690); and Alt-6 (murine IgGI,
specifically binds to prostate specific antigen (PSA); ATCC No. HB-12526).
A "multi-epitopic in vivo tumor antigen" is an antigen that present multiple
epitopes on its surface. Some non-limiting examples of such antigens include
CA125,
MUC-1, PSA, CA] 9.9, and TAG-72.
"Inducing a host immune response" means that the patient experiences
alleviation or reduction of signs or symptoms of illness, and specifically
includes,
without limitation, prolongation of survival. In certain preferred embodiments
of the
methods according to the invention, a CD8+ IFN-Ty producing T cell is
activated to
induce a cytotoxic T lymphocyte (CTL) immune response in the patient
administered
the murine monoclonal antibody. In certain embodiments of the methods
according
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to the invention, a CD4+ IFN-y producing T cell is activated to induce a
helper T cell
immune response in the patient administered with the composition. These
activated
CD4+IFN-y producing T cells (i.e., helper T cells) provide necessary
immunological
help (e.g. by release of cytokines) to induce and maintain not only CTL, but
also a
humoral immune response mediated by B cells. Thus, in certain embodiments of
the
methods according to the invention, a humoral response to the antigen is
activated in
the patient administered with the composition.
Activation of a CD8+ and/or CD4+ IFN-y producing T cells means causing T
cells that have the ability to produce IFN-y to actually produce IFN-y, or to
increase
their production of IFN-y. "Induction of CTL" means causing potentially
cytotoxic T
lymphocytes to exhibit antigen specific cytotoxicity. "Antigen specific
cytotoxicity"
means cytotoxicity against a cell presenting an antigen that is associated
with the
antigen associated with the cancer that is greater than an antigen that is not
associated
with the cancer. "Cytotoxicity" refers to the ability of the cytotoxic T
lymphocyte to
kill the target cell. Preferably, such antigen-specific cytotoxicity is at
least 3-fold,
more preferably 10-fold greater, more preferably more than 100-fold greater
than
cytotoxicity against a cell not presenting the antigen not associated with the
cancer.
In a fifth aspect, the invention includes a method for treating cancer,
comprising concurrent administration of a chemotherapeutic drug, a binding
agent,
and an antigen.
In a sixth aspect, the invention provides a method for inducing a host immune
response in a patient against a multi-epitopic in vivo tumor antigen, which
antigen
does not elicit an effective host immune response, comprising concurrently
administering to the patient a chemotherapeutic drug and a composition
comprising a
binding agent present in an amount of from 0.1 gg to 2mg per kg of body weight
of
the host, and wherein the binding agent specifically binds to an epitope on
the antigen
and an effective host immune response is elicited against a second epitope on
the
antigen.
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Example I
Clinical and Immunologic Outcomes of Patients with Recurrent Epithelial
Ovarian
Cancer (EOC) treated with B43.13 and Chemotherapy (Ct)-- Interim immunology
and
clinical results from study OVA-Gy-12.
Patients with recurrence after platinum therapy and a first surgery and were
enrolled if they were candidates for secondary surgery and continued
chemotherapy.
Alt-2 was administered by 20-minute infusion in weeks 1, 3, 5, and 9 prior to
initiation of chemotherapy, and then an option to continue every 8 weeks x 2
doses
concurrent with chemotherapy on weeks 12 and 26. Humoral immune responses,
including HAMA, Ab2 and anti-CA125 antibody, were assessed at baseline and
serially. Using gamma-interferon ELISPOT assay, T cell responses were
evaluated for
activation by Alt-2, CA125, orautologous tumor.
patients were enrolled; median follow-up was 6 months ranging up to 2
years. Alt-2 was well tolerated and did not produce drug-related serious
adverse
15 reactions. In 14 of 19 (71 %) evaluable patients, robust treatment-emergent
humoral
responses were observed to the constant (HAMA) and variable region of the
antibody
(Ab2). To date, 5 of 8 (62.5%) patients tested demonstrated functionally
active T
cells, stimulated by CAI 25 or by autologous tumor. T cell responses to Alt-2
were
demonstrated in 4 patients. T cell responses were MHC class I and II
restricted,
20 indicating the activation of CTL (cytotoxic T lymphocytes) and T helper
cells.
Immune responses were commonly induced by wk 12 after 4 doses, and were
generally maintained in patients continuing combined treatment with Alt-2 and
chemotherapy. 75% are still alive and median survival has not been reached at
120
weeks.
Conclusions: Alt-2 is well tolerated and induces multiple antigen-specific
immune
responses, even when combined with chemotherapy. In advanced EOC, these data
are among the first to demonstrate induction of tumor-specific T cells.
