AT500649A1 - COMBINATION THERAPY FOR DISEASE TREATMENT - Google Patents

Description

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COMBINATION THERAPY FOR DISEASE TREATMENT

BACKGROUND OF THE INVENTION 10 Field of the Invention

The invention relates to immunology. In particular, the invention relates to the use of immunotherapy in combination with chemotherapy.

Summary of the Related Art 15 Despite the progress that modern medicine has made in the treatment of cancer, the recurrence of cancer remains a concern. For a majority of cancers, a typical treatment involves surgery, followed by chemotherapy in high dosages. A majority of these patients relapse and do not respond to other chemotherapeutic treatments. These patients then make use of experimental or rescue treatments.

Current experimental protocols focus on a mix of chemotherapies, in an attempt to overcome resistance problems. Most of these treatments lead to serious blood toxicity such as neutropenia and thrombocytopenia. Other serious and frustrating symptoms for the patient include hair loss and nausea. Thirty researchers are now seeking ways to boost the immune system with less toxic agents while still eliminating the cancer. # »* · ··

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Many have turned to the use of chemotherapy in conjunction with antibody treatments. Many of these have also shown similar toxicities to chemotherapy. Thus, there remains a need to identify new treatments that not only treat the initial symptoms of a disease, but also mitigate and / or prevent the recurrence of these symptoms.

BRIEF SUMMARY OF THE INVENTION In a first aspect, the invention provides a method for the treatment of cancer, comprising the simultaneous administration of a xenotypic monoclonal antibody and a chemotherapeutic drug to a patient suffering from cancer. Preferably, the patient is a human.

In a second aspect, the invention provides a method of treating cancer comprising surgical cancer removal, co-administering a chemotherapeutic drug and a xenotypic monoclonal antibody in a dose equal to or less than 2 mg.

In a third aspect, the invention provides a method of treating cancer comprising surgical cancer removal, administration of a xenotypic monoclonal antibody at weeks 1, 3, 5, 9, followed by co-administration of a chemotherapeutic drug and a xenotypic monoclonal antibody at week 12, in a dose equal to or less than 2 mg.

In a fourth aspect, the invention provides a method of inducing a host immune response in a patient against • · · · · ·

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An in vivo turoric antigen with multiple epitopes ready, wherein the antigen does not elicit an effective host immune response, comprising administering to the patient a chemotherapeutic drug and a composition comprising 5 a binding agent that specifically binds to a first epitope on the antigen, and allowing the binding agent to form a binder / antigen pair, thereby causing a host immune response against a second epitope on the antigen.

In a fifth aspect, the invention provides a method of treating cancer comprising coadministering a chemotherapeutic drug, a binder and an antigen.

In a sixth aspect, the invention provides a method of inducing a host immune response in a patient against an in vivo multi-epitope tumor antigen, wherein the antigen does not elicit an effective host immune response, comprising administering to the patient a chemotherapeutic drug and a composition comprising a binder present in an amount of from 0.1 pg to 2 20 mg per kg of body weight of the host and wherein the binding agent specifically binds to an epitope on the antigen and produces an effective host immune response against a second epitope on the antigen.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a table showing the results of three clinical studies in which Alt-2 is co-administered with a chemotherapeutic drug.

Figure 2 is a diagram showing a non-limiting embodiment of the invention. ···· Μ

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Figure 3 is a graph showing the difference in numbers between Ab2 responders (white squares) (effective immune response) and Ab2 non-responders (black squares) (non-effective immune response) over time. Figure 4 is a table showing the different disease characteristics of Ab2 responders and Ab2 non-responders.

DETAILED DESCRIPTION

The present invention stems from the discovery that a combination of immunotherapy with conventional chemotherapy and / or radiotherapy mitigates and / or prevents the recurrence of cancer. The presence of a host response in a patient to a xenotypic antibody will stimulate an immune response. The inventors have exploited this discovery to develop therapeutics containing excipients useful in immunotherapy and chemotherapeutic or radiotherapeutic drugs, as well as methods of using these therapeutics. The patents and publications cited herein reflect the level of expertise in the art and are hereby incorporated in their entirety, to the same extent as would be said to be specific and individual to each and every one of them Reference is made. In the event of a conflict between a cited document and this description, this description shall prevail.

In a first aspect, the invention provides a method for the treatment of cancer, comprising the simultaneous administration of a xenotypic monoclonal antibody and a chemotherapeutic drug to a patient suffering from cancer. In some embodiments of the invention, the binding of the xenotypic monoclonal ···· ♦ ·

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Antibody to a first single epitope releases a second separate epitope on the antigen. In some embodiments of the invention, the xenotypic monoclonal antibody, when bound to the antigen, forms an immunogenic complex. Examples 5 of xenotypic monoclonal antibodies ("MAb") preferably include IgG1 antibodies, chimeric monoclonal antibodies (" C-MAb "), humanized antibodies, engineered monoclonal antibodies (" G-MAb "), fragments of monoclonal antibodies

Antibodies (including but not limited to " F (Ab) 2 ", 10 " F (Ab) " and " Dab "), and single chains, which are the reactive ones

Represent proportion of monoclonal antibodies (" SC-MAb "). The binder may be labeled or unmarked.

When the subject is a human, preferred xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibody. Particularly preferred murine monoclonal antibodies include Alt-1 (mouse IgG1 specifically binds to MUC-1, ATCC No. PTA-975, American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex® mAb B43.13, IgG1 from mouse, binds specifically to CA125, ATCC No. ΡΤΆ-1883), Alt3 20 (mouse IgG3, binds specifically to CA19.9, ATCC No. PTA-2691), Alt-4 (mouse IgM) binds specifically CA19.9, ATCC No. PTA-2692), Alt-5 (mouse IgG1, binds specifically to CA19.9, ATCC No. PTA-2690), and mouse Alt-6 (mouse IgG1) specifically binds to prostate-specific Antigen (PSA); ATCC No. HB-25 12526).

The methods of the invention are useful for providing therapeutic benefit to patients afflicted with cancer. As used herein, the term " cancer " a condition in which a cell in the body of a patient undergoes abnormal, uncontrolled proliferation. The abnormal cell may proliferate to form a solid tumor or may proliferate to form a variety of cells (e.g., leukemia). It should be noted that the term is the normal proliferation of a ········· φφ · φ η φ · φφ · · Φ ··· «· · · ♦ ··· · φ •« · · · · F Φ Φ Φ Φ Φ ΦΦΦ ΦΦ

Cell, such as a stem cell or a spermatocyte, because cancer is the abnormal, uncontrolled proliferation of a patient's cell.

By " treating a patient suffering from cancer ", 5, it is understood that the symptoms of the patient after treatment according to the invention are alleviated. By way of non-limiting example, a patient suffering from a highly metastatic cancer (e.g., breast cancer) is treated with either no additional metastases 10 or reduced in number as compared to a non-treated patient. In another non-limiting example, a patient is treated in which the size of the solid tumor of the patient is either reduced or not increased in size as compared to a non-treated patient. In yet another non-limiting example, the number of cancer cells (e.g., leukemia cells) in a treated patient either does not increase, or it is reduced as compared to the number of cancer cells in a patient receiving no treatment. In preferred embodiments, the patient is a human.

It will be appreciated that a " patient suffering from cancer ", according to the invention, can express the mutated protein and still need not be symptomatic of the disease. For example, if the cancer is a colon cancer (associated with the mutant K-ras protein), a patient with a mutant K-ras protein in some cells of the colon is a patient according to the invention, although the patient is not yet symptomatic of colon cancer his 30 must. " associated with a mutated protein " means that disease signs or symptoms are present in a majority of patients when the mutant protein is present in the patient's body, but none

Disease signs or symptoms are present when the

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Preferably, the therapeutic compositions of the invention further comprise a pharmaceutically acceptable carrier. Under a " pharmaceutically acceptable carrier " is understood to mean a carrier that is physiologically acceptable to the patient to whom it is administered. An example of a 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 (18th ed., Ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990). 15 " Administer " As used herein, delivering the composition to the patient means in a manner that results in the composition being within the body of the patient. Such administration may be by any route including, without limitation, parenteral, subcutaneous, intradermal, intravenous, intraarterial, 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, HCL-liposome injection, topotecan, hydrochloride, gemcitabine, cyclophosphamide and etoposide or any combination thereof.

In preferred embodiments, the chemotherapeutic drug is administered within one week before or after the mouse monoclonal antibody.

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In a second aspect, the invention provides a method of treating cancer comprising surgery, administering a chemotherapeutic drug, administering a xenotypic monoclonal antibody at a dose of 5 equal to or less than 2 mg administered by 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 administration of the vehicle. In certain non-limiting embodiments of the invention, the xenotypic antibody, e.g. Alt-2, administered as a 2 mg dose dissolved in 50 ml saline and slowly infused preferably for approximately 20 minutes. If an allergic reaction or other reaction occurs which may limit the complete administration of the dose, then a lower dose may be used at that time, or with subsequent treatments, so that the expected dose range would be 1-2 mg per treatment. Typically, premedication with 25 to 50 mg of diphenhydramine is administered orally or intravenously to reduce the risk of allergic reactions to the protein. The treatment regimen used for a combination of Alt-2 and chemotherapy involves administering Alt-2 in the above 25 dose at weeks 1, 3, 5, 7, 9, wherein

Chemotherapy with Alt-2 at weeks 12 to 26 is administered. Alt-2 may be started after recovery from any required surgery performed prior to chemotherapy, and it is continued thereafter until and during the treatment period of chemotherapy.

Chemotherapy may be given in cycles of 3-4 weeks, or other treatment plans, according to the attending physician and standard clinical practice. Chemotherapy can be continued for up to six cycles, followed by administration 9

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Xenotypic antibody every twelve weeks for up to two years.

In a third aspect, the invention provides a method for the treatment of cancer, comprising surgery followed within seven days by administration of a xenotypic monoclonal antibody in a dose equal to or less than 2 mg administered by intravenous infusion over 20 minutes during the course of Weeks 1, 3, 5, 9, then every 8 weeks, with concomitant administration of a chemotherapeutic drug at week 3 or thereafter.

In another non-limiting example, the mouse antibody is administered at week 1 after standard surgery has been completed but chemotherapy has not yet begun. The mouse antibody is administered at a dose equal to or less than 2 mg by a 20 minute intravenous infusion, followed by a second treatment and coadministration of a chemotherapeutic drug at week 6 and later. " Simultaneous administration " means an administration in a relatively short period of time to each other. Preferably, such a period is less than 2 weeks, more preferably less than 7 days, most preferably less than 1 day and the administration could even be simultaneous.

The expected survival times without disease progression can be measured in months to years, depending on prognostic factors, including the number of relapses, disease stage and other factors. Total survival times are also measured in months to years. In ovarian cancer, it is expected that the addition of the xenotypic monoclonal antibody Alt-2 will increase the time to onset or progression of the disease, as well as over-10 10 ···· ··· ·· ♦ ········································································································································································································································································ Any improvement of 2 months or longer is usually considered clinically meaningful.

In a fourth aspect, the invention provides a method for inducing a host immune response in a patient against a multi-epitope tumor antigen present in vivo in the host's serum, wherein the antigen is not

Induces a host immune response, comprising administering to the patient a chemotherapeutic drug and a composition comprising a binding agent that specifically binds to an epitope on the antigen, and allowing the binding agent to form a binding agent / antigen pair, wherein a host immune response against second epitope on the antigen is evoked. Examples of multi-epitope antigens are described in Nicodemus C.F. et al., Expert 15 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), and incorporated herein by reference.

A " binder " as used herein refers to a component of a binding pair comprising an immunological pair, e.g. a binding moiety capable of binding an antigen preferably a single epitope expressed on the antigen, such as a predetermined tumor antigen. In some embodiments of the invention, binding of a first single epitope exposes a second distinct epitope on the antigen. In some embodiments of the invention, when bound to the antigen, the binding agent forms an immunogenic complex. Examples of binders include, but are not limited to: antibodies, monoclonal antibodies ("MAb"), preferred IgG1 antibodies, chimeric monoclonal antibodies ("C-MAb"), humanized antibodies, engineered monoclonal antibodies (" Mb " G-MAb "), fragments of monoclonal antibodies (including but not limited to " F (Ab) 2 ", " F (Ab) " and " Dab "), single chains representing the reactive portion. · Ι · · · ι

Of monoclonal antibodies (" SC-MAb "), antigen-binding peptides, tumor-binding peptides, a protein,      ,       comprising receptor proteins, peptide, polypeptide, glycoprotein, lipoprotein or the like, eg Growth factors, lymphokines and cytokines, enzymes, immunomodulators, hormones, for example somatostatin, any of the foregoing, linked to a protein conferring effector function, and compounds which mimic any of the above, or fragments of any of the foregoing. The binder may be marked or unmarked.

Preferred binders of the invention are monoclonal antibodies. If the patient is a human, these xenotypic monoclonal antibodies include, without limitation, murine monoclonal antibodies. Particularly preferred murine monoclonal antibodies include Alt-1 (mouse IgG1 specifically binds to MUC-1, ATCC No. PTA-975, American Type Culture Collection, Manassas, VA), Alt-2 (OvaRex® mAb B43.13 .

Mouse IgGl; binds specifically to CA125; ATCC No. PTA-1883),

Alt-3 (mouse IgG3, binds specifically to CA19.9; ATCC No. 20 PTA-2691), Alt-4 (mouse IgM, binds specifically to CA19.9; ATCC No. PTA-2692), Alt-5 Mouse IgG1 binds specifically to CA19.9, ATCC No. PTA-2690), and mouse Alt-6 (IgG1) specifically binds to prostate-specific antigen (PSA) ATCC No. HB-12526). 25 One "in vivo tumor antigen with multiple epitopes"; is an antigen that presents multiple epitopes on its surface. Some non-limiting examples of such antigens include CA125, MUC-1, PSA, CA19.9, and TAG-72. " inducing a host immune response " means that the patient experiences relief or reduction of disease signs or symptoms, and specifically, without limitation, extends the survival time. In certain preferred embodiments of the invention

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Method, a CD8 + IFN-γ producing T cell is activated, wherein an immune response of cytotoxic T lymphocytes (CTL) is induced in the patient to whom the mouse monoclonal antibody has been administered. In certain embodiments of the methods of the invention, a CD4 + IFN-γ producing T cell is activated, wherein an immune response of helper T cells is induced in the patient to whom the composition has been administered. These activated CD4 + IFN-γ producing T cells (ie helper T-10 cells) provide immunological support (eg, by the release of cytokines) to induce and maintain not only CTL, but also a humoral one Immune response mediated by B cells. Thus, in certain embodiments of the inventive method, a humoral response to the antigen is activated in the patient to whom the composition has been administered.

Activation of CD8 + and / or CD4 + IFN-γ producing T cells means that T cells that can produce IFN-γ are caused to actually produce IFN-γ or to increase their production of IFN-γ increase. A " CTL Induction " means causing potentially cytotoxic T lymphocytes to actually show antigen-specific cytotoxicity. An " antigen-specific cytotoxicity " means cytotoxicity to a cell presenting a 25 antigen associated with the antigen associated with the cancer that is greater than an antigen not associated with the cancer. &Quot; 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 the cytotoxicity to a cell that does not present the antigen associated with the cancer. 13 ···· ♦♦ ·················· ········

In a fifth aspect, the invention provides a method of treating cancer comprising coadministering a chemotherapeutic drug, a binder and an antigen. In a sixth aspect, the invention provides a method for inducing a host immune response in a patient to an in vivo tumor antigen with multiple epitopes, wherein the antigen does not elicit an effective host immune response comprising simultaneously administering to the patient a chemotherapeutic drug and composition, comprising a binder present in an amount of from 0.1 pg to 2 mg 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 against a second epitope on the antigen is elicited ,

Example I

Clinical and immunological outcomes of patients with recurrent ovarian epithelial cancer (EOC) after treatment with B43.13 and chemotherapy (CT) Immunological and clinical interim results from the OVA-Gy-12 study

Patients with a relapse after platinum therapy and a first surgery were enrolled if they were candidates for 25 a second surgery and a continued chemo. Alt-2 was administered by infusion at weeks 1, 3, 5, and 9 for 20 minutes prior to the initiation of chemotherapy, and thereafter optionally every 8 weeks x 2 doses continued, concurrently with chemotherapy at weeks 12 and 26. 30 Humoral immune responses comprising the antibodies HAMA, Ab2 and CA125 were measured as baseline and serially. Under 14 14 ► · · · · · ···· • · 4 ·································· · «♦

Using the gamma-interferon ELISPOT assay, T cell responses were evaluated for activation by Alt-2, CA125 or autologous tumor. Twenty patients were enrolled, the mean follow-up period was 6 months and lasted up to 2 years. Alt-2 was well tolerated and did not produce any serious drug-related adverse reactions. In 14 of 19 evaluable patients (71%) were robust humoral

Treatment emergent responses to the constant (HAMA) and 10 variable region of the antibody (Ab2) were observed. So far, 5 out of 8 patients tested (62.5%) showed functionally active T cells stimulated by CA125 or autologous tumor. T cell responses to Alt-2 were shown in 4 patients. T cell responses were restricted to MHC class I and II, suggesting activation of CTL (cytotoxic T lymphocytes) and T helper lines. Immune responses were typically induced at week 12 after 4 doses and were generally maintained in patients who continued combination treatment with Alt-2 and chemotherapy. 20 75% are still alive, and after 120 weeks a median survival has not been achieved.

Conclusion: Alt-2 is well tolerated and induces multiple antigen-specific immune responses, even when combined with chemotherapy. For advanced EOC, these data are among the first to show the induction of tumor-specific T cells. 25

Claims (37)

A method for the treatment of cancer, comprising the simultaneous administration of a xenotypic monoclonal antibody and a chemotherapeutic drug to a patient suffering from cancer. 2. The method of claim 1, wherein the mouse xenotypic monoclonal antibody is. The method of claim 2, wherein the antibody is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-6. 4. The method of claim 1, wherein the patient is a human. The method of claim 1 or 3, wherein the chemotherapeutic agent is administered within one week prior to the mouse monoclonal antibody. 6. The method of claim 1 or 3, wherein the chemotherapeutic agent is administered within one week after the monoclonal antibody. The method of claim 1 or 3, wherein the antibody is administered at a dose of less than or equal to 2 mg. The method of claim 2, further comprising surgical removal of cancer. A method of treating cancer comprising surgical removal of cancer, concomitant administration of a chemotherapeutic drug, and administration of a chemotherapeutic drug and the administration of a chemotherapeutic drug. Xenotypic monoclonal antibody in a dose equal to or less than 2 mg............ The method of claim 9, wherein the monoclonal antibody is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-6. The method of claim 9, wherein the antibody is administered by means of a 20 minute intravenous infusion. 12. The method of claim 9, wherein the chemotherapeutic drug is administered within seven days prior to the monoclonal antibody administration. The method of claim 9, wherein the chemotherapeutic drug is administered within seven days after the administration of the monoclonal antibody. The method of claim 12 or 13, wherein the chemotherapeutic drug is administered every four weeks for six cycles. The method of claim 14, wherein the method further comprises the step of administering the xenotypic monoclonal antibody every twelve weeks for up to two years. The method of claim 15, wherein the xenotypic monoclonal antibody and the chemotherapeutic drug are administered at weeks 1, 4 and 8, followed by further administration of the chemotherapeutic drug 25 alone at weeks 12 and 16, followed by concomitant administration of the chemotherapeutic drug and the xenotypic monoclonal antibody at week 20. 17. The method of claim 9, wherein the simultaneous administration of the xenotypic monoclonal antibody 17 17 And the chemotherapeutic drug at week 1, followed by administration of the chemotherapeutic drug at week 4, repeated for six cycles, and followed by administration of the xenotype monoclonal antibody every twelve weeks for up to two years. 18. A method of treating cancer in a patient, comprising surgical cancer removal, administration of a xenotypic monoclonal antibody at weeks 10 1, 3, 5, 7 and 9, followed by co-administration of a chemotherapeutic drug and a xenotypic monoclonal antibody in a single dose of less than or equal to 2 mg in week 12. The method of claim 13, wherein the simultaneous administration of the chemotherapeutic drug and the xenotypic monoclonal antibody is repeated every four weeks for up to 6 cycles. 20. The method of claim 14, further comprising the step of administering the xenotypic monoclonal antibody every twelve weeks for up to two years. The method of claim 11, wherein the monoclonal antibody is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-6. 22. A method of inducing a host immune response in a patient to an in vivo multi-epitope tumor antigen, wherein the antigen does not elicit an effective host immune response, comprising administering to the patient a chemotherapeutic drug and a composition comprising a binder, the speci Bind the first epitope on the antigen, and allow the binder to form a binder / antigen pair. ♦♦ · ··· • • • # causing a host immune response against a second epitope on the antigen. The method of claim 22, wherein the xenotypic mouse monoclonal antibody is. The method of claim 23, wherein the antibody is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-β. 25. The method of claim 22, wherein the patient is a human. The method of claim 22, wherein the chemotherapeutic drug is administered within one week prior to the mouse monoclonal antibody. The method of claim 22, wherein the chemotherapeutic drug is administered within one week of the monoclonal antibody. 28. The method of claim 22, wherein the antibody is administered in a dose equal to or less than 2 mg. The method of claim 22, further comprising surgical cancer removal. A method of treating cancer comprising coadministering a chemotherapeutic drug, a binder and an antigen. The method of claim 30, wherein the binding agent is a mouse monoclonal antibody. 32. The method of claim 30, wherein the antibody is selected from the group consisting of Alt-1, Alt-2, Alt-3, Alt-4, Alt-5 and Alt-6. ··· # ·· · · • · ♦ # · I ··· · · »♦ * · · · · · · · · · · · · · · · · · · · 33. The method of claim 30, wherein the patient is a human. 34. The method of claim 31, wherein the chemotherapeutic agent is administered within one week prior to the monoclonal antibody from a mouse. 35. The method of claim 31, wherein the chemotherapeutic agent is administered within one week of the monoclonal antibody. 36. The method of claim 31, wherein the antibody is administered in a dose equal to or less than 2 mg. 37. A method for inducing a host immune response in a patient to an in vivo tumor antigen having a plurality of epitopes wherein the antigen does not elicit an effective host immune response comprising co-administering to the 15 patients a chemotherapeutic drug and a composition comprising a binding agent is present in an amount of from 0.1 μg to 2 mg 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 to a second epitope on the antigen is elicited.