AU2002358246B2

AU2002358246B2 - Combination therapy for treating disease

Info

Publication number: AU2002358246B2
Application number: AU2002358246A
Authority: AU
Inventors: Christopher F. Nicodemus; Antoine Noujaim; Birgit C. Schultes
Original assignee: Oncoquest Pharmaceuticals Inc
Current assignee: DIAC Co Ltd
Priority date: 2001-10-26
Filing date: 2002-10-28
Publication date: 2008-02-28
Anticipated expiration: 2022-10-28
Also published as: AT500649A1; NO20042166L; CH696871A5; GB2397018B; WO2003034977A2; CA2464947C; ES2304264A1; CA2464947A1; GB2397018A; GB0409191D0; DE10297379T5; WO2003034977A3

Description

00 -1- SCOMBINATION THERAPY FOR TREATING DISEASE (Ni Cc BACKGROUND OF THE INVENTION Field of the invention The invention relates to immunology. More particularly the invention relates to 00 V) the use of immunotherapy in combination with chemotherapy.

O Summary of the Related Art Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Despite the progress that modem 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.

00 C-i BRIEF SUMMARY OF THE INVENTION SAccording to a first aspect of the invention there is provided a method for treating cancer, comprising concurrently administering to a patient suffering from cancer a chemotherapeutic drug, and a composition comprising a xenotypic monoclonal antibody.

00 According to a second aspect of the invention there is provided a method for t treating cancer, comprising: S(1) surgically removing the cancer, concurrently administering: a composition consisting essentially of a xenotypic monoclonal antibody in a dose equal to or less than 2 mg, and a chemotherapeutic drug.

According to a third aspect of the invention there is provided a method for treating cancer in a patient, comprising: surgically removing the cancer, administering a composition consisting essentially of a xenotypic monoclonal antibody on weeks 1, 3, 5, 7 and 9 followed by concurrently administering a chemotherapeutic drug and the composition, said xenotypic monoclonal antibody in the composition is administered in a dose less than or equal to 2 mg on week 12.

According to a fourth aspect of the invention there is provided 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 first 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.

According to a fifth aspect of the invention there is provided a method for treating cancer, comprising concurrently administering a chemotherapeutic drug, a binding agent, and an antigen.

00 -3- 0 According to a sixth aspect of the invention there is provided a method for Sinducing a host immune response in a patient against a multi-epitopic in vivo tumor Santigen, which antigen does not elicit an effective host immune response, comprising concurrently administering to the patient: O 5 a chemotherapeutic drug; 00 a first composition comprising a binding agent present in an amount of from C 0.1 [tg to 2 mg per kg of body weight of the host; and Swherein 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.

According to a seventh aspect of the invention there is provided use of a chemotherapeutic drug and a composition comprising a xenotypic monoclonal antibody for the manufacture of a medicament for the treatment of cancer.

According to an eighth aspect of the invention there is provided use of a chemotherapeutic drug, a binding agent, and an antigen for the manufacture of a medicament for the treatment of cancer.

According to a ninth aspect of the invention there is provided use of a chemotherapeutic drug and a composition consisting essentially of a xenotypic antibody for the manufacture of a medicament for the treatment of cancer.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

WO 03/034977 PCT/IB02/05794 4 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.

00

O

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 response in a patient will stimulate an immune response. The inventors have exploited Sthis discovery to develop therapeutics containing binding agents useful in 00 immunotherapy and chemotherapeutic or radiotherapeutic drugs, as well as methods for aC using these therapeutics. The patents and publications cited herein reflect the level of 0 skill in this field and are hereby incorporated by reference in their entirety to the same

C

10 extent as if each was specifically and individually indicated to be incorporated by reference. In the case of any conflict between a cited reference and this specification, this specification shall prevail.

In one or more embodiments 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 preferably include IgG1 antibodies; chimeric monoclonal antibodies humanized antibodies; genetically engineered monoclonal antibodies fragments of monoclonal antibodies (including but not limited to "F(Ab) 2 and and single chains representing the reactive portion of monoclonal antibodies 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-1 (murine IgG 1, specifically binds to MUC-1; ATCC No. PTA-975; American Type Culture Collection, Manassas, VA), WO 03/034977 PCT/IB02/05794 6 Alt-2 (OvaRex@ MAb B43.13, murine IgG 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), (murine IgGI, specifically binds to CA19.9; ATCC No. PTA-2690); and Alt-6 (murine IgG 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 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 nonlimiting example, a patient suffering from a highly metastatic cancer 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 nonlimiting 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 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 00 0 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 Sa 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 IN manifestations or indications of disease.

00 Preferably, the therapeutic compositions of the invention further comprise a CI pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant 0 Sa carrier that is physiologically acceptable to the administered patient. One exemplary pharmaceutically acceptable carrier is physiological saline. Other pharmaceuticallyacceptable carriers and their formulations are well-known and generally described in, for example, Remington's pharmaceutical Sciences 18 t 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, subcutaneous, 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 one or more embodiments 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 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.

00 -8- 0 In certain, non-limiting embodiments of the invention, the xenotypic antibody, Se.g. Alt-2 is administered as a 2 mg dose dissolved in 50 mL saline and infused slowly Spreferably 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 00 usually administered to lessen the risk of allergic reaction to the protein. The schedule Cc 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 CNI 10 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 one or more embodiments 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" 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 00 -9- 0 case of ovarian cancer, the addition of the xenotypic monoclonal antibody, Alt-2 is Sexpected to increase the time to recurrence or progression, and may also prolong the Ssurvival time. Any improvement of 2 months or longer is usually considered to be clinically meaningful.

IO 5 In one or more embodiments, the invention provides a method for inducing a N host immune response in a patient against a multi-epitopic in vivo tumor antigen in 00 OO itr present in the host serum, which antigen does not elicit a host immune response, C comprising administering to the patient a chemotherapeutic drug and a composition 0 Scomprising a binding agent that specifically binds to a first epitope ton 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 and herein incorporated by reference in Nicodemus C.F. et al, Expert Rev. Vaccines 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, 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 preferably IgGI antibodies; chimeric WO 03/034977 PCT/IB02/05794 monoclonal antibodies humanized antibodies; genetically engineered monoclonal antibodies fragments of monoclonal antibodies (including but not limited to "F(Ab) 2 and single chains representing the reactive portion of monoclonal antibodies antigen-binding peptides; tumor-binding peptides; a protein, including receptor proteins; peptide; polypeptide; glycoprotein; lipoprotein, or the like, 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.

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-1 (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 CA 9.9; ATCC No. PTA-2691), Alt-4 (murine IgM, specifically binds to CA19.9; ATCC No. PTA-2692), Alt-5 (murine IgG1, 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, CA19.9, 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-y 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 00 -11- 1 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 CCD4+IFN-y producing T cells helper T cells) provide necessary immunological help 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 S methods according to the invention, a humoral response to the antigen is activated in the 00 patient administered with the composition.

M Activation of a CD8+ and/or CD4+ IFN-y producing T cells means causing T 0 cells that have the ability to produce IFN-y to actually produce IFN-y, or to increase their

C

10 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 one or more embodiments, the invention includes a method for treating cancer, comprising concurrent administration of a chemotherapeutic drug, a binding agent, and an antigen.

In one or more embodiments, 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 pg 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.

WO 03/034977 PCT/IB02/05794 12 Example I Clinical and Immunologic Outcomes of Patients with Recurrent Epithelial Ovarian Cancer (EOC) treated with B43.13 and Chemotherapy Interim immunology and clinical results from study OVA-Gv-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, or autologous 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 reactions. In 14 of 19 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 patients tested demonstrated functionally active T cells, stimulated by CA125 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, 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.

Claims

1. A method for treating cancer, comprising concurrently administering to a patient suffering from cancer a chemotherapeutic drug, and a composition comprising a xenotypic monoclonal antibody, wherein concurrent administration is as herein defined. 5 2. The method according to claim 1, wherein the composition consists essentially of C I the xenotypic monoclonal antibody. 00

3. The method according to claim 1 or claim 2, wherein the xenotypic monoclonal antibody is an unlabeled xenotypic monoclonal antibody.

4. The method according to any one of claims 1 to 3, wherein the xenotypic monoclonal antibody is murine. The method according to any one of claims 1 to 4, wherein the xenotypic monoclonal antibody is selected from the group consisting of: Alt-1 which is producible by a hybridoma having ATCC deposit number PTA-975, Alt-2 which is producible by a hybridoma having ATCC deposit number PTA-1883, Alt-3 which is producible by a hybridoma having ATCC deposit number PTA-2691, Alt-4 which is producible by a hybridoma having ATCC deposit number PTA-2692, Alt-5 which is producible by a hybridoma having ATCC deposit number PTA-2690, and Alt-6 which is producible by a hybridoma having ATCC deposit number HB12526.

6. The method according to any one of claims 1 to 5, wherein the patient is human.

7. The method according to any one of claims 1 to 6, wherein the chemotherapeutic is administered within a week before the composition.

8. The method according to any one of claims 1 to 6 wherein the chemotherapeutic is administered within a week after the composition.

9. The method according to any one of claims 1 to 8, wherein the xenotypic monoclonal antibody in the composition is administered in a dose of less than or equal to 2 mg. The method according to any one of claims 1 to 9, further comprising surgically 00 -14- O removing the cancer. S11. A method for treating cancer, comprising: surgically removing the cancer, concurrently administering: 5 a composition consisting essentially of a xenotypic monoclonal NI antibody in a dose equal to or less than 2 mg, and 00 a chemotherapeutic drug, C I wherein concurrent administration is as herein defined. O

12. The method according to claim 11, wherein the xenotypic monoclonal antibody is an unlabeled xenotypic monoclonal antibody.

13. The method according to claim 11 or claim 12, wherein the xenotypic monoclonal antibody is selected from the group consisting of: Alt-1 which is producible by a hybridoma having ATCC deposit number PTA-975, Alt-2 which is producible by a hybridoma having ATCC deposit number PTA-1883, Alt-3 which is producible by a hybridoma having ATCC deposit number PTA-2691, Alt-4 which is producible by a hybridoma having ATCC deposit number PTA-2692, Alt-5 which is producible by a hybridoma having ATCC deposit number PTA-2690, and Alt-6 which is producible by a hybridoma having ATCC deposit number HB 12526.

14. The method according to any one of claims 11 to 13, wherein the administration of the composition is over a 20-minute intravenous infusion. The method according to any one of claims 11 to 14, wherein the chemotherapeutic drug is administered within seven days prior to the administration of the composition.

16. The method according to any one of claims 11 to 14, wherein the chemotherapeutic drug is administered within seven days following the administration of the composition.

17. The method according to claim 15 or claim 16, wherein the chemotherapeutic drug is administered every four weeks for six cycles. 00 00 O 18. The method according to claim 17, wherein the method further comprises the ,d step of administration of the xenotypic monoclonal antibody every twelve weeks for up Sto two years.

19. The method according to claim 18, wherein the xenotypic monoclonal antibody and chemotherapeutic drug are administered on weeks 1, 4, and 8, followed by further Sadministration of the chemotherapeutic drug alone on weeks 12 and 16, followed by 00 0t concurrent administration of the chemotherapeutic drug and xenotypic monoclonal antibody on week 20, wherein concurrent administration is as herein defined. I 20. The method according to any one of claims 11 to 14, wherein the concurrent administration of the xenotypic monoclonal antibody and the chemotherapeutic drug occurs on week 1, followed by administration of the chemotherapeutic drug on week 4, repeated for six cycles and followed by administration of the xenotypic monoclonal antibody every twelve weeks for up to two years, wherein concurrent administration is as herein defined.

21. A method for treating cancer in a patient, comprising: surgically removing the cancer, administering a composition consisting essentially of a xenotypic monoclonal antibody on weeks 1, 3, 5, 7 and 9 followed by concurrently administering a chemotherapeutic drug and the composition, said xenotypic monoclonal antibody in the composition is administered in a dose less than or equal to 2 mg on week 12, wherein concurrent administration is as herein defined.

22. The method according to claim 21, wherein the xenotypic monoclonal antibody is an unlabeled xenotypic monoclonal antibody.

23. The method according to claim 16, wherein the concurrent administration of the chemotherapeutic drug and the composition is repeated every four weeks for up to 6 cycles, wherein concurrent administration is as herein defined.

24. The method according to claim 17, further comprising administering the composition every twelve weeks for up to two years. 00 -16- O 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 Cresponse, comprising concurrently administering to the patient a chemotherapeutic drug _and a first 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 INO pair, wherein a host immune response is elicited against a second epitope on the antigen, 00 wherein concurrent administration is as herein defined. CI 26. The method according to claim 25, wherein the first composition comprises a 0second composition consisting essentially of a monoclonal antibody or a fragment thereof that specifically binds to a first epitope on the antigen and allowing the monoclonal antibody or fragment thereof to form a monoclonal antibody or fragment thereof/ antigen pair.

27. The method according to claim 25 or claim 26, wherein the monoclonal antibody is an unlabeled monoclonal antibody.

28. The method according to claim 25 or claim 26, wherein the monoclonal antibody is a murine xenotypic monoclonal antibody.

29. The method according to any one of claims 25 to 28, wherein the monoclonal antibody is selected from the group consisting of: Alt-1 which is producible by a hybridoma having ATCC deposit number PTA-975, Alt-2 which is producible by a hybridoma having ATCC deposit number PTA-1883, Alt-3 which is producible by a hybridoma having ATCC deposit number PTA-2691, Alt-4 which is producible by a hybridoma having ATCC deposit number PTA-2692, Alt-5 which is producible by a hybridoma having ATCC deposit number PTA-2690, and Alt-6 which is producible by a hybridoma having ATCC deposit number HB12526.

30. The method according to any one of claims 25 to 29, wherein the patient is human.

31. The method according to any one of claims 25 to 30, wherein the chemotherapeutic drug is administered within a week before the monoclonal antibody.

32. The method according to any one of claims 25 to 30, wherein the chemotherapeutic drug is administered within a week after the monoclonal antibody. 00 -17- O

33. The method according to any one of claims 25 to 32, wherein the antibody is Sadministered in a dose of equal to or less than 2 mg. tn 34. The method according to any one of claims 25 to 33, further comprising surgically removing the cancer.

35. A method for treating cancer, comprising concurrently administering a 00 chemotherapeutic drug, a binding agent, and an antigen, wherein concurrent Cc administration is as herein defined. S36. The method according to claim 35, wherein the binding agent is a monoclonal antibody or a fragment thereof that binds the antigen.

37. The method according to claim 35 or claim 36, wherein the binding agent is a murine monoclonal antibody.

38. The method according to claim 36 or claim 37, wherein the monoclonal antibody is selected from the group consisting of: Alt-1 which is producible by a hybridoma having ATCC deposit number PTA-975, Alt-2 which is producible by a hybridoma having ATCC deposit number PTA-1883, Alt-3 which is producible by a hybridoma having ATCC deposit number PTA-2691, Alt-4 which is producible by a hybridoma having ATCC deposit number PTA-2692, Alt-5 which is producible by a hybridoma having ATCC deposit number PTA-2690, and Alt-6 which is producible by a hybridoma having ATCC deposit number HB 12526.

39. The method according to any one of claims 35 to 38, wherein the patient is human. The method according to any one of claims 35 to 39, wherein the chemotherapeutic drug is administered within a week before the murine monoclonal antibody.

41. The method according to any one of claims 35 to 39, wherein the chemotherapeutic drug is administered within a week after the monoclonal antibody.

42. The method according to any one of claims 36 to 41, wherein the antibody is administered in a dose of equal to or less than 2 mg. 00 -18- 0 S43. 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 Sresponse, comprising concurrently administering to the patient: a chemotherapeutic drug; a first composition comprising a binding agent present in an amount of from 0.1 pgg to 2 mg per kg of body weight of the host; and 00 wherein the binding agent specifically binds to an epitope on the antigen and an 00 effective host immune response is elicited against a second epitope on the antigen, wherein concurrent administration is as herein defined.

44. The method according to claim 43, wherein the first composition comprises a second composition consisting essentially of a xenotypic monoclonal antibody or a fragment thereof, and wherein the xenotypic monoclonal antibody or fragment thereof specifically binds to an epitope on the antigen and an effective host immune response is elicited against a second epitope on the antigen.

45. The method according to claim 44, wherein the second composition consisting essentially of the xenotypic monoclonal antibody is an unlabeled xenotypic monoclonal antibody.

46. A method for treating cancer, comprising concurrently administering a composition consisting essentially of a xenotypic antibody and a chemotherapeutic drug to a patient suffering from cancer, wherein concurrent administration is as herein defined.

47. The method according to claim 46, wherein the composition consisting essentially of the xenotypic antibody is an unlabeled xenotypic antibody.

48. The method according to claim 46 or claim 47, wherein the xenotypic antibody in the composition is administered in a dose of less than or equal to 2 mg.

49. The method according to any one of claims 1 to 34, 36 to 42 and 44 to 48, wherein the antibody is an IgGl antibody. Use of a chemotherapeutic drug and a composition comprising a xenotypic monoclonal antibody for the manufacture of a medicament for the treatment of cancer. 00 -19- 0

51. Use of a chemotherapeutic drug, a binding agent, and an antigen for the Smanufacture of a medicament for the treatment of cancer. C4 tn 52 Use of a chemotherapeutic drug and a composition consisting essentially of a xenotypic antibody for the manufacture of a medicament for the treatment of cancer.

53. A method for treating cancer comprising concurrently administering to a patient 00 suffering from cancer a chemotherapeutic drug, and a composition comprising a r xenotypic monoclonal antibody; a method for treating cancer according to claim I I or claim 21; a method for inducing a host immune response in a patient against a multi- ,i epitopic in vivo tumor antigen, which antigen does not elicit an effective host immune response; a method for treating cancer, comprising concurrently administering a chemotherapeutic drug, a binding agent, and an antigen; use of a chemotherapeutic drug and a composition for the manufacture of a medicament for the treatment of cancer; use of a chemotherapeutic drug, a binding agent, and an antigen for the manufacture of a medicament for the treatment of cancer; or use of a chemotherapeutic drug and a composition consisting essentially of a xenotypic antibody for the manufacture of a medicament for the treatment of cancer, substantially as herein described with reference to any one or more of the examples but excluding comparative examples, wherein concurrent administration is as herein defined.