WO2016180781A1 - Combination therapy of mesothelioma - Google Patents
Combination therapy of mesothelioma Download PDFInfo
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- WO2016180781A1 WO2016180781A1 PCT/EP2016/060336 EP2016060336W WO2016180781A1 WO 2016180781 A1 WO2016180781 A1 WO 2016180781A1 EP 2016060336 W EP2016060336 W EP 2016060336W WO 2016180781 A1 WO2016180781 A1 WO 2016180781A1
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Definitions
- the present invention relates to a method of treating and/or preventing malignant mesothelioma comprising administering a combination of an effective amount of a DNA hypomethylating agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
- DNA hypomethylating agents may be of potential clinical use also as immunomodulatory compounds capable of combining with a variety of new immunotherapeutic agents.
- mAb monoclonal antibodies
- CTLA-4 anti-cytotoxic T-lymphocyte associated antigen 4
- mAb ipilimumab represents the prototype of this new category of molecules. Ipilimumab has received regulatory approval since it significantly prolonged the survival of metastatic melanoma patients. 12 ' 13 - 14 In spite being ipilimumab monotherapy presently the mainstay for first-line immunotherapy in melanoma, only 20% of the patients experience long term survival. 12 ' 13 Thus, ongoing clinical trials are exploring novel therapeutic combinations to improve its clinical efficacy.
- Malignant mesothelioma is a lethal tumor mainly caused by the exposure to asbestos, with a steadily increasing incidence worldwide 35 .
- Malignant mesothelioma is classified into 3 broad histological subtypes: epithelioid, sarcomatoid, and biphasic, comprising approximately 50% to 70%, 10% to 20%, and 20% to 40% of malignant mesothelioma, respectively.
- Patients with the sarcomatoid or biphasic subtype have a poor outcome compared to the epithelioid subtype 36 .
- Pleural malignant mesothelioma is the most common anatomical site (67% to 75%) of presentation, followed by peritoneal (25% to 33%) that has a slightly better prognosis than pleural malignant mesothelioma 37 , pericardium or tunica vaginalis testis are very rarely presentation.
- the average interval between onset of symptoms and diagnosis is 2 to 3 months 35 , and almost 80%> -90%> of the patients will present with unresectable disease at diagnosis and rely on palliative treatment.
- the median survival of untreated malignant mesothelioma patients is 6 to 9 months with less than 5% of patients surviving 5 years.
- Prognostic factors associated with better outcome are earlier stage and epithelioid histological type, as well as asymptomatic disease, better performance status, younger age, and absence of weight loss.
- Pemetrexed and platinum combination therapy is currently regarded as the standard of care for first-line treatment of pleural malignant mesothelioma in the advanced disease setting 38 ' 39 ; however, the outcome of malignant mesothelioma patients remains dismal, with a response rate of 30-40%; a median time to progression of 5.7 months, and a median overall survival from diagnosis of 12.1 months 40 .
- DNA hypomethylating agents could represent potential pharmacologic partners to improve the therapeutic activity of CTLA-4 blocking mAb by taking advantage of the functional immunomodulatory activity of these compounds on neoplastic and immune cells, respectively.
- the inventors investigated the therapeutic and immunologic aspects of 5-AZA-CdR in combination with CTLA-4 blockade utilizing two syngeneic murine transplantable cancer models. Inventors' results show a significant anti-tumor activity of this combination that warrants being explored in the clinical setting.
- DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells.
- the inventors predicted they could be utilized to design new immunotherapeutic combinations in cancer.
- the anti-tumor efficacy of the DNA hypomethylating agent 5-aza-2'- deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated.
- mice were injected subcutaneously in the flank region with murine mammary carcinoma TS/A (BALB/c, athymic nude and SCID/Beige) or murine malignant mesothelioma ABl (BALB/c) cells and treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues.
- TS/A murine mammary carcinoma TS/A
- SCID/Beige murine mammary carcinoma TS/A
- mAb 9H10 murine malignant mesothelioma ABl
- 5-AZA-CdR-based regimens induced a promoter- demethylation- sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR.
- the DNA hypomethylating agent is selected from the group consisting of: 5- azacytidine, 5-aza-2'-deoxycytidine (5-AZA-CdR), zebularine, procainamide, procaine, hydralazine, epigallocathechin-3-gallate, RG108, MG98.
- the immunomodulatory agent is selected from the group consisting of: immunomodulating antibody, cancer vaccine, therapeutic cytokine, cellular therapy.
- the immunomodulating antibody is selected from the group consisting of: an anti-CTLA-4, an anti-PDL-1, an anti-PDL-2, an anti-PDl, an anti-CD 137, an anti-CD40, anti- LAG3, anti-TIM3, anti-KIR, anti-GITR, anti-ICOS or an anti-OX-40 antibody.
- an anti-CTLA-4 an anti-CTLA-4, an anti-PDL-1, an anti-PDL-2, an anti-PDl, an anti-CD 137, an anti-CD40, anti- LAG3, anti-TIM3, anti-KIR, anti-GITR, anti-ICOS or an anti-OX-40 antibody.
- an anti-CTLA-4 an anti-CTLA-4, an anti-PDL-1, an anti-PDL-2, an anti-PDl, an anti-CD 137, an anti-CD40, anti- LAG3, anti-TIM3, anti-KIR, anti-GITR, anti-ICOS or an anti-OX-40 antibody.
- Any type of antibody may be
- the cancer vaccine is selected from the group consisting of: cellular vaccines, including antigen presenting cells loaded with cancer relevant antigens or tumor cell lysates; whole tumor antigen protein- or peptide-based vaccines; vector-based vaccines where plasmid DNA and viral, bacterial, yeast vectors are used to deliver tumor-associated antigens; anti-idiotypic antibodies, inhibitors of angiogenesis (Butterfield L., Cancer Vaccine, BMJ 2015; 350).
- the therapeutic cytokine is selected from the group consisting of: GM-CSF, IL-2, IL-12, IL-17, TNF a, IFN ⁇ or IFN a.
- the cellular therapy is selected from the group consisting of: T cells, stem cells, dendritic cells, gene- or pharmacologically-modified immune and/or cancer cells.
- the targeted therapy agent is selected from the group consisting of: a MAP kinase pathway inhibitor, a WNT pathway inhibitor, an IDO inhibitor and a JAK inhibitor.
- the MAP kinase pathway inhibitor is selected from the group consisting of : a BRAF inhibitor, a MEK inhibitor, a PI3K inhibitor or a c-KIT inhibitor.
- the BRAF inhibitor is selected from the group consisting of: GDC-0879, PLX-4720, Sorafenib Tosylate, dabrafenib or LGX818.
- the MEK inhibitor is selected from the group consisting in: GSK1120212, selumetinib or MEK162.
- the WNT pathway inhibitor is selected from the group consisting of: a beta catenin inhibitor or a frizzled inhibitor.
- the beta catenin inhibitor is selected from the group consisting of: niclosamide, XAV-939, FH 535 or ICG 001.
- the DNA hypomethylating agent is 5-AZA-CdR and the immunomodulating antibody is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
- the malignant mesothelioma is resistant or refractory to at least one anti-tumor therapy.
- DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally the least one targeted therapy agent are administered simultaneously or sequentially.
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of malignant mesothelioma.
- the pharmaceutical composition further comprises an anti-tumoral agent.
- an anti-tumoral agent is selected from the group consisting of: pemetrexed, platinum, cisplatin, carboplatin, gemcitabine, Ipilimumab or a combination thereof
- the invention provides a kit comprising a DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of malignant mesothelioma wherein the DNA hypomethylating agent and the at least one immunomodulatory agent and/or optionally the at least one targeted therapy agent are in separated containers.
- the invention provides a method of treating and/or preventing malignant mesothelioma comprising administering an effective amount of a DNA hypomethylating agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
- the DNA hypomethylating agent is 5-AZA-CdR and the immunomodulatory agent is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
- malignant mesothelioma is an aggressive cancer affecting the membrane lining of the lungs and abdomen.
- Malignant mesothelioma is the most serious of all asbestos-related diseases. Exposure to asbestos is the primary cause and risk factor for mesothelioma.
- Pleural malignant mesothelioma is the most common anatomical site (67% to 75%) of presentation, followed by peritoneal (25% to 33%). Pericardium or tunica vaginalis testis are very rarely presentation. There are three main histological types of malignant mesothelioma:
- malignant mesothelioma comprises any form of the disease such as pleural and peritoneal mseothelioma as well as resistant form thereof.
- the DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent are administered simultaneously or sequentially.
- the DNA hypomethylatmg agent may be administered before or after the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent.
- a pharmaceutical composition comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of cancer, as defined above.
- kits comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of cancer wherein the DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the at least one targeted therapy agent are in separated containers or in the same container.
- Any of the DNA hypomethylatmg agent, immunomodulatory agent or targeted therapy agent may be in powder form (for instance lyophilized) that can be dissolved in an appropriate solvent.
- It is a further object of the invention a method of treating and/or preventing cancer comprising administering an effective amount of a DNA hypomethylatmg agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
- the agents being defined as above.
- the DNA hypomethylatmg agent is 5-AZA-CdR and the immunomodulatory agent is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
- a DNA hypomethylatmg agent may be a compound able to inhibit DNA methyltransferase activity reversing aberrant hypermethylation of a multitude of genes, restoring their expression and functional activity (Sigalotti L et al. Epigenetic drugs as immunomodulators for combination therapies in solid tumors Pharmacol Ther. 2013 Dec 30.).
- An immunomodulatory agent is defined as a compound that induces or increases immunogenicity and immune recognition of cancer cells by host's immune system.
- a targeted therapy agent is defined as compound that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth.
- a Mitogen-activated protein kinase kinase (MEK) inhibitor e.g., GSK1120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2- chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),
- MEK162 (5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)- 1 -methyl- 1 H- benzo[d]imidazole-6-carboxamide)) is a chemical compound that inhibits Mitogen-activated protein kinase kinase enzymes.
- a Phosphoinositide 3-kinase (PI3K) inhibitor e.g., Wortmannin (1 l-(acetyloxy)-lS,6bPv,7,8,9aS,10,l 1R,1 lbR-octahydro-l-(methoxymethyl)-9a,l lb-dimethyl- 3H-furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione
- LY294002 (2-Morpholin-4-yl-8- phenylchromen-4-one), perifosine (l,l-Dimethylpiperidinium-4-yl octadecyl phosphate)
- PI3K inhibitor e.g., Wortmannin (1 l-(acetyloxy)-lS,6bPv,7,8,9aS,10,l 1R,1 lbR-octahydro-l-
- a c-KIT inhibitor e.g., nilotinib (4-methyl-N-[3-(4-methyl-lH-imidazol-l- yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide), imatinib (4- [(4-methylpiperazin- 1 -yl)methyl] -N-(4-methyl-3 - ⁇ [4-(pyridin-3 -yl)pyrimidin-2- yl]amino ⁇ phenyl)benzamide))
- imatinib 4- [(4-methylpiperazin- 1 -yl)methyl] -N-(4-methyl-3 - ⁇ [4-(pyridin-3 -yl)pyrimidin-2- yl]amino ⁇ phenyl)benzamide
- Refractory or resistant cancer is defined as a cancer that does not respond to existing anticancer therapy or treatment (i.e., chemotherapy, radiation therapy, targeted therapies).
- existing therapies may be a chemotherapy drug including: Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin)
- Adrucil Injection (5-FU (fluorouracil)) , Afinitor (Everolimus) , Afmitor Disperz (Everolimus) , Alimta (PEMETREXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU
- Kyprolis (Carfilzomib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection
- Radiotherapy means the use of radiation, usually X-rays, to treat illness. X-rays were discovered in 1895 and since then radiation has been used in medicine for diagnosis and investigation (X-rays) and treatment (radiotherapy). Radiotherapy may be from outside the body as external radiotherapy, using X-rays, cobalt irradiation, electrons, and more rarely other particles such as protons. It may also be from within the body as internal radiotherapy, which uses radioactive metals or liquids (isotopes) to treat cancer.
- Targeted therapy may be enzyme inhibitors such as Tyrosine kinase inhibitors, mTOR inhibitors, Proteosome inhibitors, Growth factor inhibitors, Signal-transduction inhibitors, Multi-targeted kinase molecule which blocks many different enzymes. It may also be called a multikinase inhibitor. Some targeted therapies change proteins within the cancer cells and cause the cells to die. These are called apoptosis-inducing drugs. Targeted therapy included also angiogenesis inhibitors, working for instance by blocking vascular endothelial growth factor, also called VEGF.
- VEGF is a family of protein growth factors made by some tumors. The VEGF proteins can attach to the VEGF receptors of blood vessel cells. This causes new blood vessels to form around the tumors. Blocking this process prevents angiogenesis, which would form new blood vessels to feed tumors so they could grow.
- the term "effective amount” shall mean an amount which achieves a desired effect or therapeutic effect as such effect is understood by those of ordinary skill in the art.
- the DNA hypomethylating agent and the immunomodulatory agent may be administered simultaneously or sequentially and they may be administered with a targeted therapy agent that may replace the immunomodulatory agent.
- compositions containing the DNA hypomethylating agent and the immunomodulatory agent and/or optionally the targeted therapy agent of the present invention may be manufactured by processes well known in the art, e.g., using a variety of well-known mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- the compositions may be formulated in conjunction with one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Parenteral routes are preferred in many aspects of the invention.
- the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as physiological saline buffer or polar solvents including, without limitation, a pyrrolidone or dimethylsulfoxide.
- physiologically compatible buffers such as physiological saline buffer or polar solvents including, without limitation, a pyrrolidone or dimethylsulfoxide.
- the compounds are preferably formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers.
- Useful compositions include, without limitation, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents.
- Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle.
- Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes.
- Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxym ethyl cellulose, sorbitol, or dextran.
- the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
- the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well-known in the art.
- Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, pastes, slurries, solutions, suspensions, concentrated solutions and suspensions for diluting in the drinking water of a patient, premixes for dilution in the feed of a patient, and the like, for oral ingestion by a patient.
- Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores.
- Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropyl- methylcellulose, sodium carboxy- methylcellulose, and/or polyvinylpyrrolidone (PVP).
- disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used.
- the compounds of the present invention can conveniently be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant
- the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
- the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
- the compounds may be delivered using a sustained-release system, such as semi- permeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials have been established and are well known by those skilled in the art.
- Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the particular compound, additional stabilization strategies may be employed.
- Other delivery systems such as liposomes and emulsions can also be used.
- a therapeutically effective amount refers to an amount of compound effective to prevent, alleviate or ameliorate cancer symptoms. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the disclosure herein.
- the therapeutically effective amount can be estimated initially from in vitro assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the effective dosage. Such information can then be used to more accurately determine dosages useful in patients.
- the amount of the composition that is administered will depend upon the parent molecule included therein. Generally, the amount used in the treatment methods is that amount which effectively achieves the desired therapeutic result in mammals. Naturally, the dosages of the various compounds can vary somewhat depending upon the compound, rate of in vivo hydrolysis, etc. In addition, the dosage, of course, can vary depending upon the dosage form and route of administration.
- DNA hypomethylating agent and immunomodulatory agent administration should follow the current clinical guidelines.
- the immunomodulatory agent may be administered as the immunotherapeutic mAb, ipilimumab or tremelimumab.
- the DNA hypomethylating agent described herein can be administered in amounts ranging from about 0.1 to about 3000 mg/m 2 , preferably from about 0.1 to 1500 mg/m 2 , still preferably from 1 to about 1000 mg/m 2 , yet preferably from 1 to about 500 mg/m 2 , yet preferably from 1 to about 200 mg/m 2 , yet preferably from 1 to about 100 mg/m 2 , yet preferably from 10 to about 100 mg/m 2 .
- the immunomodulating antibody described herein can be administered in amounts ranging from about 0.1 to about 60 mg/kg and preferably from about 0.1 to about 20 mg/ kg, still preferably from about 0.2 to about 10 mg/kg, yet preferably from about 0.6 to about 6 mg/kg. Still preferably about 3 mg/kg.
- the range set forth above is illustrative and those skilled in the art will determine the optimal dosing of the compound selected based on clinical experience and the treatment indication. Moreover, the exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition and of the most effective route of administration (e.g., intravenous, subcutaneous, intradermal). Additionally, toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals using methods well- known in the art. In one embodiment, the treatment of the present invention includes administering the compounds described herein in an amount of from about 0.3 to about 6 mg/kg/dose to a mammal with a cancer.
- the amounts of the compounds administered can be based on body surface of human or other mammals.
- the amounts of the compounds described herein range from about 0.2 to about 25 mg/m 2 dose/body surface.
- Some preferred doses include one of the following: 1.25, 2.0, 2.5, 3.3, 5, 10, and 16.5 mg/m 2 .
- the amounts administered can range from about 1.25 to about 16.5 mg/m 2 body surface/dose.
- they can be from about 2.5 to about 13 mg/m 2 body surface/dose or from about 2 to about 5 mg/m 2 body surface/dose.
- the treatment protocol can be based on a single dose administered once every three weeks or divided into multiple doses which are given as part of a multi-week treatment protocol.
- the treatment regimens can include one dose every three weeks for each treatment cycle and, alternatively one dose weekly for three weeks followed by one week off for each cycle.
- a preferred dose is one dose every twelve weeks.
- the precise dose and schedule of administration will depend on the stage and severity of the condition, and the individual characteristics of the patient being treated, as well as the most effective biological activity of treatment as will be appreciated by one of ordinary skill in the art. It is also contemplated that the treatment continues until satisfactory results are observed, which can be as soon as after 1 cycle although from about 3 to about 6 cycles or more cycles may be required such as in a maintenance schedule of administration.
- the treatment protocol includes administering the amount ranging from about 1.25 to about 16.5 mg/m 2 body surface/dose every three weeks repeating for about 3 cycles or more.
- the amount administered per each cycle can range more preferably from about 2.5 to about 16.5 mg/m 2 body surface/dose.
- the compounds described herein can be administered weekly for three weeks, followed by one week without treatment and repeating for about 3 cycles or more until the desired results are observed.
- a preferred dose for the immunomodulatory agent is 3 mg/kg intravenously in 90 minutes every 3 weeks for 4 doses. Another preferred dose for the immunomodulatory agent is 15 mg/kg intravenously every 90 days for 4 dose. Another preferred dose for the immunomodulatory agent is 10 mg/kg once every 4 weeks for six doses 43 .
- the treatment will be given for one or more cycles until the desired clinical and biological result is obtained.
- the exact amount, frequency and period of administration of the compound of the present invention will vary, of course, depending upon the sex, age and medical condition of the patient as well as the severity and type of the disease as determined by the attending clinician.
- Still further aspects include combining the therapy described herein with other anticancer therapies for synergistic or additive benefit.
- the schedule of treatment with the combinations can foresee that the DNA hypomethylating agent (DHA) is administered concomitantly, before and/or after any of the "partner" immunomodulatory agent (eg, immunomodulatory mAb, vaccines, etc, etc) identified above.
- the dose of DHA and of the "partner" immunomodulatory agent (eg, immunomodulatory mAb, vaccines, etc, etc) identified above can cover a wide range of concentrations.
- Combination therapies can be utilized for advanced stage of disease but also, prospectively, in the adjuvant and neo-adjuvant setting.
- mice were inoculated sc with 2> ⁇ 10 5 TS/A cells.
- Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h); on days 0, 7 (1 st cycle) and 42, 49 (2 nd cycle); with mAb 9H10 10( ⁇ g on days 2, 5, 8 (1 st cycle) and 44, 47, 50 (2 nd cycle); with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control.
- Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volume for each group are reported. Vertical arrows indicate days of different treatments.
- FIG. 1 A) Total RNA was extracted from tumors excised from TS/A grafted mice treated with: saline solution, as control group (CTRL), mAb 9H10 100 ⁇ g, 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h), or the combination of 5-AZA-CdR with mAb 9H10.
- RT-PCR analysis was performed using P1A-, Mage-a- or jS-actm-specific primer pairs. PCR products were then separated on a 2% agarose gel and visualized by ethidium bromide staining.
- RNA from mouse testis and splenocytes was utilized as positive (ctrl +) or negative (ctrl -) controls respectively.
- Figure shows data from three representative mice out of five for control and treated groups.
- Real-time quantitative Methylation-Specific PCR analyses of P1A promoter were performed on bisulfite-modified genomic DNA, extracted from 3 out of 5 mice per group, using methylated- or unmethylated-specific primer pairs. Data are reported as percentage of average methylation that was defined as the ratio between methylated molecules and the sum of methylated and unmethylated molecules. Bars, SD; *, p ⁇ 0.05 vs. control group.
- FIG. 3 Modulation of MHC class I antigen expression and T cell infiltration by 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model.
- BALB/c mice were inoculated sc with 2> ⁇ 10 5 TS/A cells.
- Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h); with mAb 9H10 10( ⁇ g; with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control.
- a week after the end of treatment neoplastic and normal tissues were excised and snap frozen in liquid nitrogen.
- A-F MHC class I staining of tumors from mice treated with saline solution, with mAb 9H10 or 5-AZA-CdR, respectively
- D, E, F CD3 staining of tumors from mice treated with saline solution, with mAb 9H10 or the combination of 5-AZA-CdR and with mAb 9H10, respectively
- G, H, I, L, M, N CD3 staining of glandular epithelium of large intestine, liver, lung, myocardium renal parenchima and dermis from mice treated with mAb 9H10 or 5-AZA-CdR, respectively.
- A-F 200 X magnification, G-M, 160 X magnification; N, 250 X magnification.
- the arrowed marks the dermal-epidermal junction
- Athymic nude mice (A) and SCID/Beige (B) mice were inoculated sc with 2> ⁇ 10 5 TS/A cells.
- Groups of 4 mice, for each strains, were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0 and 7; with mAb 9H10 100 ⁇ g on days 2, 5, 8; with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control.
- Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volumes for each group are reported. Vertical arrows indicate days of different treatments. *, p ⁇ 0.05; **, p ⁇ 0.01 vs. tumor volume of control group.
- mice were inoculated sc with 3x 10 6 AB1 cells.
- Groups of 3 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0, 7; mAb 9H10 100 ⁇ g on days 2, 5, 8; combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or saline solution for control.
- Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volumes for each group are reported. Vertical arrows indicate days of different treatments. *, p ⁇ 0.05 vs. tumor volume of control group.
- FIG. 6 Immunohistochemical analysis of T cell infiltration by 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model.
- BALB/c mice were inoculated sc with 2x l0 5 TS/A cells.
- Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0, 7 combined with mAb 9H10 10( ⁇ g on days 2, 5, 8; or with saline solution for control.
- a week after the end of treatment neoplastic tissues were excised and snap frozen in liquid nitrogen. Four micron acetone-fixed cryostat sections were processed for IHC assays. Representative results from 3 investigated mice are reported.
- A, B CD4 and CD8 staining of tumors from mice treated with the combination of 5-AZA-CdR and mAb 9H10, respectively.
- the murine mammary carcinoma TS/A cell line established from a spontaneously originating malignancy 15 and displaying no significant transplant immunogenicity in syngeneic host, was grown in DMEM Medium (Biochrom AG, Cat # FG 0445) supplemented with 10% heat- inactivated fetal bovine serum (FBS) (Lonza, Cat # DEI 4-802), 2 mM L-glutamine (Biochrom AG, Cat # K 0282) and 50 ⁇ ⁇ -mercaptoethanol.
- FBS heat- inactivated fetal bovine serum
- the commercially available murine malignant mesothelioma AB1 cell 16 line was purchased from CellBank Australia (Cat # CBA- 0144) and grown in RPMI Medium (Biochrom AG, Cat # FG 1215) supplemented with 5% heat-inactivated FBS, and 2 mM L-glutamine .
- mice Six-week-old female BALB/c, athymic nude and SCID/Beige mice were purchased from Harlan Laboratories. Animal care and experiments were in accordance with Institutional guidelines and the indications of Workman et al. 17
- CT26.WT ATCC® CRL- 2638TM
- 3LL JCRB Cell Bank #JCRB13408
- the hamster mAb 9H10 against murine CTLA-4 was purchased from BioXCell (cat # BE0131).
- the isotype control ChromePure Syrian hamster IgG were purchased from Jackson Immuno Research (cat # 007-000-003).
- the rat mAb 10F.9G2 against murine PD-L1 (cat #BE0101), the hamster mAb J43 against murine PD-1 (cat #BE0033-2), the rat mAb C9B7W against murine LAG3 (cat # BE0174) were purchased from BioXCell.
- 5-AZA-CdR was purchased from Sigma Chemical Co. (cat # A3656).
- mice were injected subcutaneously (sc) in the flank region with TS/A (2> ⁇ 10 5 ) (BALB/c, athymic nude and SCID/Beige) or ABl (3xl0 6 ) (BALB/c) cells resuspended in 0.1 ml of physiologic saline.
- mice bearing clearly palpable and visible tumor grafts were randomly grouped and treated intraperitoneally (ip) with 0.2 ml/injection of: i) 15 mg/kg of 5-AZA-CdR (fractionated in three injections a day, every three hours) on days 0 and 7 (1 st cycle of treatment) and on days 42 and 49 (2 nd cycle of treatment); ii) 100 ⁇ g of hamster mAb 9H10, on days 2, 5 and 8 (1 st cycle of treatment) and on days 44, 47 and 50 (2 nd cycle of treatment); iii) combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules; iv) 100 ⁇ g of isotype control hamster IgG on days 2, 5 and 8; or v) combined administration of 5-AZA-CdR and hamster
- mice were injected ip with 0.2 ml of saline solution.
- the rational choice of the dose/schedule of 5-AZA-CdR utilized for these experiments derived from preliminary experiments the inventors had performed in immunocompetent and immunocompromised mice (data not shown).
- the 15 mg/kg/day regimen had the best tumor immunomodulation with no/limited mice toxicity and was therefore chosen for the in vivo experiments..
- Tumor size evaluated by caliper measurements, and body weight were recorded periodically all along the treatment.
- % of tumor growth inhibition was calculated using the formula: 100 - to TM"° lmg c M6 a m tCB :» , 100
- RNA and DNA were extracted from tissues sections, removed from TS/A tumor of control and treated mice and homogenized with the aid of Tissue Lyser II (QIAGEN) in Trizol reagent (Invitrogen, cat # 15596-026) or lysis buffer, respectively.
- Total RNA was extracted following the manufacturer's instructions and stored at -80°C.
- Total genomic DNA was extracted by digestion with 100 ⁇ g/ml proteinase K in the presence of 0.5% SDS at 50°C overnight, followed by phenol/chloroform extraction and ethanol precipitation. Genomic DNA was dissolved in TE buffer and stored at -20°C. RT-PCR analysis
- RT-PCR reactions were performed using oligonucleotide primer sequences and PCR amplification programs specific for PI A and Mage-a. 18 ' 19 The integrity of RNA and random primers-synthesized cDNA was confirmed by the amplification of all cDNA samples with mouse ?-actm-specific primers, as previously described. 6 Five ⁇ of each RT-PCR sample were run on a 2% agarose gel, stained with ethidium bromide and visualized by Gel doc XR (BioRad Laboratories).
- TTAAGTGCGTTATTACGTTTGGTTTTTAC-3' (SEQ ID No. 1), reverse 5'- ATAACCGATTATTTAATACAAAAATCGACG-3' (SEQ ID No. 2); PI A (Unmethylated), forward 5 '-GATTAAGTGTGTTATTATGTTTGGTTTTTAT-3 ' (SEQ ID No. 3), reverse 5'- ACATAACCAATTATTTAATACAAAAATCAACA-3 ' (SEQ ID No. 4).
- SYBR green quantitative Methylation-Specific PCR reactions were performed on 2 ⁇ of bisulfite-modified genomic DNA in a final volume of 25 ⁇ IX Power SYBR green mastermix (Applied Biosystems, cat # 4367659) at 95°C for 10 min, followed by 45 cycles of 15 sec at 95°C and 1 min at 60°C, using methylated- or unmethylated-specific primer pairs.
- the copy number of methylated or unmethylated sequences for the target gene was established in each sample by extrapolation from the standard curves. The percentage of methylation was defined as the ratio between methylated molecules and the sum of methylated and unmethylated molecules.
- the following antibodies were employed: polyclonal anti human CD3+ cross reacting with murine T lymphocytes (Dako, cat # A045201), anti mouse MHC class I mAb 28- 14-8S anti H2Db (ATCC HB-27) 21 and AF6-88.5.3 anti H2Kb (ATCC HB-158). 22
- Rat anti mouse CD4 (Clone H129.19 cat # 550278) and CD8a (Clone 53-6-7 cat # 563332) lymphocytes were purchased from BD Bioscience. Primary antibodies dilutions were established using normal mouse spleen sections. Samples incubated with isotype matched immunoglobulins were used as negative controls.
- mice received a 2 nd cycle of 5-AZA-CdR combined with mAb 9H10 or 5- AZA-CdR alone at day 42 (Fig. 1).
- a strong anti-tumor activity of this combination regimen was also found using a model of malignant mesothelioma, mice grafted with syngeneic AB1 mesothelioma cells (#3 mice/group).
- No reduction in tumor volumes was observed in mice treated with mAb 9H10 alone, as compared to control mice (Fig. 5).
- Immunomodulatory activity of 5-AZA-CdR combined with mAb 9H10 on TS/A tumors The immunomodulatory activity of 5-AZA-CdR combined with mAb 9H10 was investigated in TS/A tumors excised one week after the end of treatment from 3 randomly selected treated and control mice; changes in the expression of different murine Cancer Testis Antigen (i.e., tumor rejection antigen PI A (PI A) and Melanoma Antigen A (Mage-a) family members) and of MHC class I antigens were utilized as readouts.
- PI A tumor rejection antigen
- Mage-a Melanoma Antigen A
- RT-PCR unveiled a de novo expression of PI A and Mage-a members in neoplastic tissues from animals treated with 5-AZA-CdR alone or combined with mAb 9H10; in contrast, no effect was observed following treatment with the anti-CTLA-4 mAb alone (Fig. 2A).
- mice treated with 5-AZA-CdR combined with mAb 9H10 allowed a conclusive interpretation on the changes of MHC class I antigens expression only in two animals (data not shown).
- 5-AZA-CdR reduced tumor growth in both animal models (Fig 4A, B); noteworthy, no further reduction in tumor growth was detected when mAb 9H10 was added to 5-AZA-CdR monotherapy in both athymic nude mice (Fig. 4A) and SCID/Beige immunocompromised mice (Fig. 4B). Treatment of immunocompetent BALB/c mice, utilized as internal controls, led to results similar to those previously obtained (data not shown). Analysis of immune cell infiltrates in neoplastic and normal tissues
- TS/A tumor tissues randomly selected from 3 out of 5 treated and control mice, were evaluated for T cells infiltration.
- Fig. 3D Tumors from control animals displayed no necrosis and no infiltration by CD3+ lymphocytes.
- treatment with 5-AZA-CdR or with mAb 9H10 resulted in tumors with an average of 30% of necrosis and a CD3+ infiltrate of 15.2 (+/- 0.5) (data not shown), or with variable areas of necrosis and CD3+ lymphocytes infiltrate of 27 (+/- 1.7) (Fig. 3E) with a balanced presence of CD4+ and CD 8+ cells, respectively.
- mice a Treatment number b SD number b SD number b SD
- the inventors have recently demonstrated that epigenetic remodeling of TS/A tumors by 5- AZA-CdR preferentially modulated gene expression profiles belonging to immune-related pathways, 6 suggesting for a broad spectrum of immune genes and mechanisms that could contribute to improve the immunogenicity and immune-recognition of DNA hypomethylating agents -treated cancer cells. Confirming this activity of 5-AZA-CdR, in the present invention the expression of the methylation-regulated PI A gene was up-regulated exclusively in 5-AZA- CdR-containing regimens. Additional support to the broad functional immunomodulation of neoplastic cells by DNA hypomethylating agents derives from the immunohistochemical finding that the expression of MHC class I molecules was up-regulated in 5-AZA-CdR-treated tumors.
- the findings of the present invention provide a sound scientific rationale to translate the immunomodulatory activities of epigenetic drugs into the clinic, for novel and potentially more effective combinatorial immunotherapeutic strategies with immunomodulating antibodies such as anti-CTLA-4, anti-PD-1 and/or anti-PDL-1 mAb.
- Curran MA et al., Proc.Natl.Acad.Sci.U.S.A. 2010; 107(9): 4275-4280.
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Abstract
The present invention relates to a method of treating and/or preventing malignant mesothelioma comprising administering a combination of an effective amount of a DNA hypomethylating agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
Description
Combination therapy of mesothelioma
Technical Field
The present invention relates to a method of treating and/or preventing malignant mesothelioma comprising administering a combination of an effective amount of a DNA hypomethylating agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
Background art
Among the pleiotropic activities of epigenetic drugs, 1 the inventors have extensively characterized the immunomodulatory properties of DNA hypomethylating agents in human malignances of different histotype. 2'3 Exposure of neoplastic cells to these agents effectively improved T cell recognition of melanoma and renal carcinoma cells in vitro. 3'4'5 This functional effect was found to be mediated, at least in part, by the up-regulation of the expression of tumor antigens (e.g., Cancer Testis Antigens), HLA class I and accessory/co-stimulatory molecules by neoplastic cells. 3'4'6'7 To further explore the immunomodulatory potential of DNA hypomethylating agents, the inventors also demonstrated that changes in genome-wide expression profiles induced by 5-aza-2'-deoxycytidine (5-AZA-CdR) in BALB/c mice grafted with the murine mammary adenocarcinoma TS/A cells were preferentially observed in neoplastic tissues as compared to normal counterparts, and that they affected mainly immunologic pathways. 6 Supporting the immunomodulatory activity of DNA hypomethylating agents, the inventors also showed that a second-generation agent designated SGI- 110, induced the expression of different tumor-associated antigens (e.g., NY-ESO-1, MAGE-A1 and -A3) in PBMC from patients affected by myelodysplasia syndrome or acute myelogenous leukemia. 8 Overall these findings further demonstrate that DNA hypomethylating agents may be of potential clinical use also as immunomodulatory compounds capable of combining with a variety of new immunotherapeutic agents.
Among the latter, monoclonal antibodies (mAb) targeting different immune-checkpoints are emerging as powerful therapeutic tools in cancer. 9'10'n The anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) mAb ipilimumab represents the prototype of this new category of molecules. Ipilimumab has received regulatory approval since it significantly prolonged the survival of metastatic melanoma patients. 12'13-14 In spite being ipilimumab monotherapy presently the mainstay for first-line immunotherapy in melanoma, only 20% of the patients
experience long term survival. 12'13 Thus, ongoing clinical trials are exploring novel therapeutic combinations to improve its clinical efficacy.
Malignant mesothelioma is a lethal tumor mainly caused by the exposure to asbestos, with a steadily increasing incidence worldwide 35. Malignant mesothelioma is classified into 3 broad histological subtypes: epithelioid, sarcomatoid, and biphasic, comprising approximately 50% to 70%, 10% to 20%, and 20% to 40% of malignant mesothelioma, respectively. Patients with the sarcomatoid or biphasic subtype have a poor outcome compared to the epithelioid subtype 36. Pleural malignant mesothelioma is the most common anatomical site (67% to 75%) of presentation, followed by peritoneal (25% to 33%) that has a slightly better prognosis than pleural malignant mesothelioma 37 , pericardium or tunica vaginalis testis are very rarely presentation. Despite the unquestionable improvement in its diagnosis the average interval between onset of symptoms and diagnosis is 2 to 3 months 35, and almost 80%> -90%> of the patients will present with unresectable disease at diagnosis and rely on palliative treatment. The median survival of untreated malignant mesothelioma patients is 6 to 9 months with less than 5% of patients surviving 5 years. Prognostic factors associated with better outcome are earlier stage and epithelioid histological type, as well as asymptomatic disease, better performance status, younger age, and absence of weight loss. Pemetrexed and platinum combination therapy is currently regarded as the standard of care for first-line treatment of pleural malignant mesothelioma in the advanced disease setting 38' 39; however, the outcome of malignant mesothelioma patients remains dismal, with a response rate of 30-40%; a median time to progression of 5.7 months, and a median overall survival from diagnosis of 12.1 months 40. There is no approved treatment for peritoneal mesothelioma; however, pemetrexed and cisplatin/carboplatin are commonly used in first-line treatment regimens. In second-line treatment, no therapies have shown survival benefits and no agents are currently approved for pleural or peritoneal malignant mesothelioma after progression from first-line treatment 40'41. As a result, a significant unmet medical need exists in this disease setting. Along this line, recent evidence reported that a proportion of mesothelioma patients benefits long-term from treatment with the anti-CTLA-4 mAb, tremelimumab42. Summary of the invention
Based on the comprehensive evidence above, the inventors reasoned that DNA hypomethylating agents could represent potential pharmacologic partners to improve the therapeutic activity of CTLA-4 blocking mAb by taking advantage of the functional immunomodulatory activity of these compounds on neoplastic and immune cells, respectively.
To provide experimental support to this hypothesis, in this study the inventors investigated the therapeutic and immunologic aspects of 5-AZA-CdR in combination with CTLA-4 blockade utilizing two syngeneic murine transplantable cancer models. Inventors' results show a significant anti-tumor activity of this combination that warrants being explored in the clinical setting.
The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells. Thus, the inventors predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, as an example, the anti-tumor efficacy of the DNA hypomethylating agent 5-aza-2'- deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated.
Mice were injected subcutaneously in the flank region with murine mammary carcinoma TS/A (BALB/c, athymic nude and SCID/Beige) or murine malignant mesothelioma ABl (BALB/c) cells and treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues.
A significant anti-tumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p<0.01), 54% (p<0.01) and 33% (p=0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These anti-tumor activities were confirmed utilizing the ABl model, a recognized model of malignant mesothelioma. 5-AZA-CdR-based regimens induced a promoter- demethylation- sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Anti-tumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice injected with TS/A cells, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related anti-tumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients, in particular in malignant mesothelioma, colon carcinoma and lung carcinoma, preferably Lewis lung carcinoma.
Therefore the present invention provides a DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent for use in the treatment and/or in the prevention of malignant mesothelioma.
Preferably the DNA hypomethylating agent is selected from the group consisting of: 5- azacytidine, 5-aza-2'-deoxycytidine (5-AZA-CdR), zebularine, procainamide, procaine, hydralazine, epigallocathechin-3-gallate, RG108, MG98.
Preferably the immunomodulatory agent is selected from the group consisting of: immunomodulating antibody, cancer vaccine, therapeutic cytokine, cellular therapy.
Still preferably the immunomodulating antibody is selected from the group consisting of: an anti-CTLA-4, an anti-PDL-1, an anti-PDL-2, an anti-PDl, an anti-CD 137, an anti-CD40, anti- LAG3, anti-TIM3, anti-KIR, anti-GITR, anti-ICOS or an anti-OX-40 antibody. Any type of antibody may be used, the term antibody comprises also functional fragments thereof, monoclonal antibody, humanized antibody.
In a preferred embodiment the cancer vaccine is selected from the group consisting of: cellular vaccines, including antigen presenting cells loaded with cancer relevant antigens or tumor cell lysates; whole tumor antigen protein- or peptide-based vaccines; vector-based vaccines where plasmid DNA and viral, bacterial, yeast vectors are used to deliver tumor-associated antigens; anti-idiotypic antibodies, inhibitors of angiogenesis (Butterfield L., Cancer Vaccine, BMJ 2015; 350).
In a preferred embodiment the therapeutic cytokine is selected from the group consisting of: GM-CSF, IL-2, IL-12, IL-17, TNF a, IFN γ or IFN a.
In a still preferred embodiment the cellular therapy is selected from the group consisting of: T cells, stem cells, dendritic cells, gene- or pharmacologically-modified immune and/or cancer cells.
In a preferred embodiment the targeted therapy agent is selected from the group consisting of: a MAP kinase pathway inhibitor, a WNT pathway inhibitor, an IDO inhibitor and a JAK inhibitor.
Preferably the MAP kinase pathway inhibitor is selected from the group consisting of : a BRAF inhibitor, a MEK inhibitor, a PI3K inhibitor or a c-KIT inhibitor. Still preferably the BRAF inhibitor is selected from the group consisting of: GDC-0879, PLX-4720, Sorafenib Tosylate, dabrafenib or LGX818. Yet preferably the MEK inhibitor is selected from the group consisting in: GSK1120212, selumetinib or MEK162.
Preferably, the WNT pathway inhibitor is selected from the group consisting of: a beta catenin inhibitor or a frizzled inhibitor.
Yet preferably the beta catenin inhibitor is selected from the group consisting of: niclosamide, XAV-939, FH 535 or ICG 001.
In a preferred embodiment the DNA hypomethylating agent is 5-AZA-CdR and the immunomodulating antibody is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
In a preferred embodiment the malignant mesothelioma is resistant or refractory to at least one anti-tumor therapy.
In a preferred embodiment the DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally the least one targeted therapy agent are administered simultaneously or sequentially.
In a further aspect the invention provides a pharmaceutical composition comprising a DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of malignant mesothelioma.
Preferably the pharmaceutical composition further comprises an anti-tumoral agent. Preferably such anti-tumoral agent is selected from the group consisting of: pemetrexed, platinum, cisplatin, carboplatin, gemcitabine, Ipilimumab or a combination thereof
In a further aspect the invention provides a kit comprising a DNA hypomethylating agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of malignant mesothelioma wherein the DNA hypomethylating agent and the at least one immunomodulatory agent and/or optionally the at least one targeted therapy agent are in separated containers.
In a further aspect the invention provides a method of treating and/or preventing malignant mesothelioma comprising administering an effective amount of a DNA hypomethylating agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
Preferably the DNA hypomethylating agent is 5-AZA-CdR and the immunomodulatory agent is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
In the present invention malignant mesothelioma is an aggressive cancer affecting the membrane lining of the lungs and abdomen. Malignant mesothelioma is the most serious of all asbestos-related diseases. Exposure to asbestos is the primary cause and risk factor for mesothelioma.
Pleural malignant mesothelioma is the most common anatomical site (67% to 75%) of presentation, followed by peritoneal (25% to 33%). Pericardium or tunica vaginalis testis are very rarely presentation.
There are three main histological types of malignant mesothelioma:
• (1) Epithelioid mesothelioma (tubulo-papillary);
• (2) Sarcomatoid mesothelioma;
• (3) Biphasic mesothelioma (Mixed mesothelioma).
In the present invention malignant mesothelioma comprises any form of the disease such as pleural and peritoneal mseothelioma as well as resistant form thereof.
In a preferred embodiment the DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent are administered simultaneously or sequentially. The DNA hypomethylatmg agent may be administered before or after the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent. It is a further object of the invention a pharmaceutical composition comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of cancer, as defined above.
It is a further object of the invention a kit comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined above for use in the treatment and/or in the prevention of cancer wherein the DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the at least one targeted therapy agent are in separated containers or in the same container. Any of the DNA hypomethylatmg agent, immunomodulatory agent or targeted therapy agent may be in powder form (for instance lyophilized) that can be dissolved in an appropriate solvent.
It is a further object of the invention a method of treating and/or preventing cancer comprising administering an effective amount of a DNA hypomethylatmg agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent. The agents being defined as above. Preferably the DNA hypomethylatmg agent is 5-AZA-CdR and the immunomodulatory agent is an anti-CTLA-4 and/or an anti-PDL-1 antibody.
In the present invention a DNA hypomethylatmg agent may be a compound able to inhibit DNA methyltransferase activity reversing aberrant hypermethylation of a multitude of genes, restoring their expression and functional activity (Sigalotti L et al. Epigenetic drugs as immunomodulators for combination therapies in solid tumors Pharmacol Ther. 2013 Dec 30.). An immunomodulatory agent is defined as a compound that induces or increases immunogenicity and immune recognition of cancer cells by host's immune system. In the present invention a targeted therapy agent is defined as compound that blocks the growth of
cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth. A Mitogen-activated protein kinase kinase (MEK) inhibitor (e.g., GSK1120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2- chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide),
MEK162 (5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)- 1 -methyl- 1 H- benzo[d]imidazole-6-carboxamide)) is a chemical compound that inhibits Mitogen-activated protein kinase kinase enzymes. A Phosphoinositide 3-kinase (PI3K) inhibitor (e.g., Wortmannin (1 l-(acetyloxy)-lS,6bPv,7,8,9aS,10,l 1R,1 lbR-octahydro-l-(methoxymethyl)-9a,l lb-dimethyl- 3H-furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione), LY294002 (2-Morpholin-4-yl-8- phenylchromen-4-one), perifosine (l,l-Dimethylpiperidinium-4-yl octadecyl phosphate)) is a potential medical drug that functions by inhibiting a Phosphoinositide 3-kinase resulting in tumor suppression. A c-KIT inhibitor (e.g., nilotinib (4-methyl-N-[3-(4-methyl-lH-imidazol-l- yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide), imatinib (4- [(4-methylpiperazin- 1 -yl)methyl] -N-(4-methyl-3 - { [4-(pyridin-3 -yl)pyrimidin-2- yl]amino}phenyl)benzamide)) is a compound that inhibits c-KIT, a tyrosine kinase enzyme, involved with the transduction and processing of many extracellular and intracellular signals including cell proliferation. Refractory or resistant cancer is defined as a cancer that does not respond to existing anticancer therapy or treatment (i.e., chemotherapy, radiation therapy, targeted therapies). Such existing therapies may be a chemotherapy drug including: Abitrexate (Methotrexate Injection), Abraxane (Paclitaxel Injection), Adcetris (Brentuximab Vedotin Injection), Adriamycin (Doxorubicin)
Adrucil Injection (5-FU (fluorouracil)) , Afinitor (Everolimus) , Afmitor Disperz (Everolimus) , Alimta (PEMETREXED), Alkeran Injection (Melphalan Injection), Alkeran Tablets (Melphalan), Aredia (Pamidronate), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arzerra (Ofatumumab Injection), Avastin (Bevacizumab), Bexxar (Tositumomab), BiCNU (Carmustine), Blenoxane (Bleomycin), Bosulif (Bosutinib), Busulfex Injection (Busulfan Injection), Campath (Alemtuzumab), Camptosar (Irinotecan), Caprelsa (Vandetanib), Casodex (Bicalutamide), CeeNU (Lomustine), CeeNU Dose Pack (Lomustine), Cerubidine (Daunorubicin), Clolar (Clofarabine Injection), Cometriq (Cabozantinib), Cosmegen (Dactinomycin), CytosarU (Cytarabine), Cytoxan (Cytoxan), Cytoxan Injection (Cyclophosphamide Injection), Dacogen (Decitabine), DaunoXome (Daunorubicin Lipid Complex Injection), Decadron (Dexamethasone), DepoCyt (Cytarabine Lipid Complex Injection), Dexamethasone Intensol (Dexamethasone), Dexpak Taperpak (Dexamethasone),
Docefrez (Docetaxel), Doxil (Doxorubicin Lipid Complex Injection), Droxia (Hydroxyurea), DTIC (Decarbazine), Eligard (Leuprolide), Ellence (Ellence (epirubicin)), Eloxatin (Eloxatin (oxaliplatin)), Elspar (Asparaginase), Emcyt (Estramustine), Erbitux (Cetuximab), Erivedge (Vismodegib), Erwinaze (Asparaginase Erwinia chrysanthemi), Ethyol (Amifostine), Etopophos (Etoposide Injection), Eulexin (Flutamide), Fareston (Toremifene), Faslodex (Fulvestrant), Femara (Letrozole), Firmagon (Degarelix Injection), Fludara (Fludarabine), Folex (Methotrexate Injection), Folotyn (Pralatrexate Injection), FUDR (FUDR (floxuridine)), Gemzar (Gemcitabine), Gilotrif (Afatinib), Gleevec (Imatinib Mesylate), Gliadel Wafer (Carmustine wafer), Halaven (Eribulin Injection), Herceptin (Trastuzumab), Hexalen (Altretamine), Hycamtin (Topotecan), Hycamtin (Topotecan), Hydrea (Hydroxyurea), Iclusig (Ponatinib), Idamycin PFS (Idarubicin), Ifex (Ifosfamide), Inlyta (Axitinib), Intron A alfab (Interferon alfa-2a), Iressa (Gefitinib), Istodax (Romidepsin Injection), Ixempra (Ixabepilone Injection), Jakafi (Ruxolitinib), Jevtana (Cabazitaxel Injection), Kadcyla (Ado -trastuzumab Emtansine),
Kyprolis (Carfilzomib), Leukeran (Chlorambucil), Leukine (Sargramostim), Leustatin (Cladribine), Lupron (Leuprolide), Lupron Depot (Leuprolide), Lupron DepotPED (Leuprolide), Lysodren (Mitotane), Marqibo Kit (Vincristine Lipid Complex Injection), Matulane (Procarbazine), Megace (Megestrol), Mekinist (Trametinib), Mesnex (Mesna), Mesnex (Mesna Injection), Metastron (Strontium-89 Chloride), Mexate (Methotrexate Injection), Mustargen (Mechlorethamine), Mutamycin (Mitomycin), Myleran (Busulfan), Mylotarg (Gemtuzumab Ozogamicin), Navelbine (Vinorelbine), Neosar Injection (Cyclophosphamide Injection), Neulasta (filgrastim), Neulasta (pegfilgrastim), Neupogen (filgrastim), Nexavar (Sorafenib), Nilandron (Nilandron (nilutamide)), Nipent (Pentostatin), Nolvadex (Tamoxifen), Novantrone (Mitoxantrone), Oncaspar (Pegaspargase), Oncovin (Vincristine), Ontak (Denileukin Diftitox), Onxol (Paclitaxel Injection), Panretin (Alitretinoin), Paraplatin (Carboplatin), Perjeta (Pertuzumab Injection), Platinol (Cisplatin), Platinol (Cisplatin Injection), PlatinolAQ (Cisplatin), PlatinolAQ (Cisplatin Injection), Pomalyst (Pomalidomide), Prednisone Intensol (Prednisone), Proleukin (Aldesleukin), Purinethol (Mercaptopurine), Reclast (Zoledronic acid), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), RoferonA alfaa (Interferon alfa-2a), Rubex (Doxorubicin), Sandostatin (Octreotide), Sandostatin LAR Depot (Octreotide), Soltamox (Tamoxifen), Sprycel (Dasatinib), Sterapred (Prednisone), Sterapred DS (Prednisone), Stivarga (Regorafenib), Supprelin LA (Histrelin Implant), Sutent (Sunitinib), Sylatron (Peginterferon Alfa-2b Injection (Sylatron)), Synribo (Omacetaxine Injection), Tabloid (Thioguanine), Taflinar (Dabrafenib), Tarceva
(Erlotinib), Targretin Capsules (Bexarotene), Tasigna (Decarbazine), Taxol (Paclitaxel Injection), Taxotere (Docetaxel), Temodar (Temozolomide), Temodar (Temozolomide Injection), Tepadina (Thiotepa), Thalomid (Thalidomide), TheraCys BCG (BCG), Thioplex (Thiotepa), TICE BCG (BCG), Toposar (Etoposide Injection), Torisel (Temsirolimus), Treanda (Bendamustine hydrochloride), Trelstar (Triptorelin Injection), Trexall (Methotrexate), Trisenox (Arsenic trioxide), Tykerb (lapatinib), Valstar (Valrubicin Intravesical), Vantas (Histrelin Implant), Vectibix (Panitumumab), Velban (Vinblastine), Velcade (Bortezomib), Vepesid (Etoposide), Vepesid (Etoposide Injection), Vesanoid (Tretinoin), Vidaza (Azacitidine), Vincasar PFS (Vincristine), Vincrex (Vincristine), Votrient (Pazopanib), Vumon (Teniposide), Wellcovorin IV (Leucovorin Injection), Xalkori (Crizotinib), Xeloda (Capecitabine), Xtandi (Enzalutamide), Yervoy (Ipilimumab Injection), Zaltrap (Ziv-aflibercept Injection), Zanosar (Streptozocin), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zoladex (Goserelin), Zolinza (Vorinostat), Zometa (Zoledronic acid), Zortress (Everolimus), Zytiga (Abiraterone).
Radiotherapy means the use of radiation, usually X-rays, to treat illness. X-rays were discovered in 1895 and since then radiation has been used in medicine for diagnosis and investigation (X-rays) and treatment (radiotherapy). Radiotherapy may be from outside the body as external radiotherapy, using X-rays, cobalt irradiation, electrons, and more rarely other particles such as protons. It may also be from within the body as internal radiotherapy, which uses radioactive metals or liquids (isotopes) to treat cancer.
Targeted therapy may be enzyme inhibitors such as Tyrosine kinase inhibitors, mTOR inhibitors, Proteosome inhibitors, Growth factor inhibitors, Signal-transduction inhibitors, Multi-targeted kinase molecule which blocks many different enzymes. It may also be called a multikinase inhibitor. Some targeted therapies change proteins within the cancer cells and cause the cells to die. These are called apoptosis-inducing drugs. Targeted therapy included also angiogenesis inhibitors, working for instance by blocking vascular endothelial growth factor, also called VEGF. VEGF is a family of protein growth factors made by some tumors. The VEGF proteins can attach to the VEGF receptors of blood vessel cells. This causes new blood vessels to form around the tumors. Blocking this process prevents angiogenesis, which would form new blood vessels to feed tumors so they could grow.
In the present invention the term "effective amount" shall mean an amount which achieves a desired effect or therapeutic effect as such effect is understood by those of ordinary skill in the art. In the present invention, the DNA hypomethylating agent and the immunomodulatory agent
may be administered simultaneously or sequentially and they may be administered with a targeted therapy agent that may replace the immunomodulatory agent.
Pharmaceutical compositions containing the DNA hypomethylating agent and the immunomodulatory agent and/or optionally the targeted therapy agent of the present invention may be manufactured by processes well known in the art, e.g., using a variety of well-known mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The compositions may be formulated in conjunction with one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Parenteral routes are preferred in many aspects of the invention.
For injection, including, without limitation, intravenous, intramusclular and subcutaneous injection, the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as physiological saline buffer or polar solvents including, without limitation, a pyrrolidone or dimethylsulfoxide.
The compounds are preferably formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers. Useful compositions include, without limitation, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuncts such as suspending, stabilizing and/or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of a water soluble form, such as, without limitation, a salt of the active compound. Additionally, suspensions of the active compounds may be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxym ethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers and/or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, pastes, slurries, solutions, suspensions, concentrated solutions and
suspensions for diluting in the drinking water of a patient, premixes for dilution in the feed of a patient, and the like, for oral ingestion by a patient. Pharmaceutical preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding other suitable auxiliaries if desired, to obtain tablets or dragee cores. Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as, for example, maize starch, wheat starch, rice starch and potato starch and other materials such as gelatin, gum tragacanth, methyl cellulose, hydroxypropyl- methylcellulose, sodium carboxy- methylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross- linked polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium alginate may also be used.
For administration by inhalation, the compounds of the present invention can conveniently be delivered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. The compounds of this invention may be formulated for this route of administration with suitable polymeric or hydrophobic materials (for instance, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a sparingly soluble derivative such as, without limitation, a sparingly soluble salt.
Additionally, the compounds may be delivered using a sustained-release system, such as semi- permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the particular compound, additional stabilization strategies may be employed. Other delivery systems such as liposomes and emulsions can also be used.
A therapeutically effective amount refers to an amount of compound effective to prevent, alleviate or ameliorate cancer symptoms. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the disclosure herein. For any compound used in the methods of the invention, the therapeutically effective amount
can be estimated initially from in vitro assays. Then, the dosage can be formulated for use in animal models so as to achieve a circulating concentration range that includes the effective dosage. Such information can then be used to more accurately determine dosages useful in patients.
The amount of the composition that is administered will depend upon the parent molecule included therein. Generally, the amount used in the treatment methods is that amount which effectively achieves the desired therapeutic result in mammals. Naturally, the dosages of the various compounds can vary somewhat depending upon the compound, rate of in vivo hydrolysis, etc. In addition, the dosage, of course, can vary depending upon the dosage form and route of administration.
In particular, DNA hypomethylating agent and immunomodulatory agent administration should follow the current clinical guidelines. For instance the immunomodulatory agent may be administered as the immunotherapeutic mAb, ipilimumab or tremelimumab.
In general, however, the DNA hypomethylating agent described herein can be administered in amounts ranging from about 0.1 to about 3000 mg/m2, preferably from about 0.1 to 1500 mg/m2, still preferably from 1 to about 1000 mg/m2, yet preferably from 1 to about 500 mg/m2, yet preferably from 1 to about 200 mg/m2, yet preferably from 1 to about 100 mg/m2, yet preferably from 10 to about 100 mg/m2.
The immunomodulating antibody described herein can be administered in amounts ranging from about 0.1 to about 60 mg/kg and preferably from about 0.1 to about 20 mg/ kg, still preferably from about 0.2 to about 10 mg/kg, yet preferably from about 0.6 to about 6 mg/kg. Still preferably about 3 mg/kg.
The range set forth above is illustrative and those skilled in the art will determine the optimal dosing of the compound selected based on clinical experience and the treatment indication. Moreover, the exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition and of the most effective route of administration (e.g., intravenous, subcutaneous, intradermal). Additionally, toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals using methods well- known in the art. In one embodiment, the treatment of the present invention includes administering the compounds described herein in an amount of from about 0.3 to about 6 mg/kg/dose to a mammal with a cancer.
Alternatively and preferably, the amounts of the compounds administered can be based on body surface of human or other mammals. Preferably, the amounts of the compounds described
herein range from about 0.2 to about 25 mg/m2 dose/body surface. Some preferred doses include one of the following: 1.25, 2.0, 2.5, 3.3, 5, 10, and 16.5 mg/m2. Preferably, the amounts administered can range from about 1.25 to about 16.5 mg/m2 body surface/dose. Alternatively, they can be from about 2.5 to about 13 mg/m2 body surface/dose or from about 2 to about 5 mg/m2 body surface/dose. The treatment protocol can be based on a single dose administered once every three weeks or divided into multiple doses which are given as part of a multi-week treatment protocol. Thus, the treatment regimens can include one dose every three weeks for each treatment cycle and, alternatively one dose weekly for three weeks followed by one week off for each cycle. A preferred dose is one dose every twelve weeks. The precise dose and schedule of administration will depend on the stage and severity of the condition, and the individual characteristics of the patient being treated, as well as the most effective biological activity of treatment as will be appreciated by one of ordinary skill in the art. It is also contemplated that the treatment continues until satisfactory results are observed, which can be as soon as after 1 cycle although from about 3 to about 6 cycles or more cycles may be required such as in a maintenance schedule of administration.
In some preferred embodiments, the treatment protocol includes administering the amount ranging from about 1.25 to about 16.5 mg/m2 body surface/dose every three weeks repeating for about 3 cycles or more. The amount administered per each cycle can range more preferably from about 2.5 to about 16.5 mg/m2 body surface/dose. Alternatively, the compounds described herein can be administered weekly for three weeks, followed by one week without treatment and repeating for about 3 cycles or more until the desired results are observed.
A preferred dose for the immunomodulatory agent is 3 mg/kg intravenously in 90 minutes every 3 weeks for 4 doses. Another preferred dose for the immunomodulatory agent is 15 mg/kg intravenously every 90 days for 4 dose. Another preferred dose for the immunomodulatory agent is 10 mg/kg once every 4 weeks for six doses43.
It is contemplated that the treatment will be given for one or more cycles until the desired clinical and biological result is obtained. The exact amount, frequency and period of administration of the compound of the present invention will vary, of course, depending upon the sex, age and medical condition of the patient as well as the severity and type of the disease as determined by the attending clinician.
Still further aspects include combining the therapy described herein with other anticancer therapies for synergistic or additive benefit.
The schedule of treatment with the combinations can foresee that the DNA hypomethylating agent (DHA) is administered concomitantly, before and/or after any of the "partner" immunomodulatory agent (eg, immunomodulatory mAb, vaccines, etc, etc) identified above. The dose of DHA and of the "partner" immunomodulatory agent (eg, immunomodulatory mAb, vaccines, etc, etc) identified above can cover a wide range of concentrations. Combination therapies can be utilized for advanced stage of disease but also, prospectively, in the adjuvant and neo-adjuvant setting.
The present invention will be illustrated by means of non-limiting examples in reference to the following figures.
Figure 1. Anti-tumor activity of 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model.
BALB/c mice were inoculated sc with 2>< 105 TS/A cells. Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h); on days 0, 7 (1st cycle) and 42, 49 (2nd cycle); with mAb 9H10 10(^g on days 2, 5, 8 (1st cycle) and 44, 47, 50 (2nd cycle); with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control. Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volume for each group are reported. Vertical arrows indicate days of different treatments. *, p<0.05; **, p<0.01; p<0.001 vs. tumor volume of control group.†, p<0.05;††, p<0.01 vs. tumor volume of 5-AZA-CdR group. Representative data are shown from three experiments.
Figure 2. Regulation of Cancer Testis Antigen expression by 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model. A) Total RNA was extracted from tumors excised from TS/A grafted mice treated with: saline solution, as control group (CTRL), mAb 9H10 100μg, 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h), or the combination of 5-AZA-CdR with mAb 9H10. RT-PCR analysis was performed using P1A-, Mage-a- or jS-actm-specific primer pairs. PCR products were then separated on a 2% agarose gel and visualized by ethidium bromide staining. Total RNA from mouse testis and splenocytes was utilized as positive (ctrl +) or negative (ctrl -) controls respectively. Figure shows data from three representative mice out of five for control and treated groups. B) genomic DNA was extracted from TS/A tumors excised from control mice (black) and mice treated with mAb 9H10 (white), 5- AZA-CdR (vertical line) or the combination of 5-AZA-CdR with mAb 9H10 (horizontal line). Real-time quantitative Methylation-Specific PCR analyses of P1A promoter were performed on bisulfite-modified genomic DNA, extracted from 3 out of 5 mice per group, using methylated- or
unmethylated-specific primer pairs. Data are reported as percentage of average methylation that was defined as the ratio between methylated molecules and the sum of methylated and unmethylated molecules. Bars, SD; *, p<0.05 vs. control group.
Figure 3. Modulation of MHC class I antigen expression and T cell infiltration by 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model. BALB/c mice were inoculated sc with 2>< 105 TS/A cells. Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h); with mAb 9H10 10(^g; with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control. A week after the end of treatment, neoplastic and normal tissues were excised and snap frozen in liquid nitrogen. Four micron acetone-fixed cryostat sections were processed for IHC assays. Representative results from tumors (panel A-F) and normal tissues (panel G-N) are reported. A, B, C: MHC class I staining of tumors from mice treated with saline solution, with mAb 9H10 or 5-AZA-CdR, respectively; D, E, F: CD3 staining of tumors from mice treated with saline solution, with mAb 9H10 or the combination of 5-AZA-CdR and with mAb 9H10, respectively; G, H, I, L, M, N: CD3 staining of glandular epithelium of large intestine, liver, lung, myocardium renal parenchima and dermis from mice treated with mAb 9H10 or 5-AZA-CdR, respectively. A-F, 200 X magnification, G-M, 160 X magnification; N, 250 X magnification. The arrowed marks the dermal-epidermal junction; black arrows, CD3+ lymphocytes.
Figure 4. Anti-tumor activity of 5-AZA-CdR combined with mAb 9H10 in immunocompromised mice.
Athymic nude mice (A) and SCID/Beige (B) mice were inoculated sc with 2>< 105 TS/A cells. Groups of 4 mice, for each strains, were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0 and 7; with mAb 9H10 100μg on days 2, 5, 8; with combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules, or with saline solution for control. Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volumes for each group are reported. Vertical arrows indicate days of different treatments. *, p<0.05; **, p<0.01 vs. tumor volume of control group.
Figure 5. Anti-tumor activity of 5-AZA-CdR combined with mAb 9H10 in the syngeneic AB1 mouse tumor model.
BALB/c mice were inoculated sc with 3x 106 AB1 cells. Groups of 3 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0, 7; mAb 9H10 100μg on days 2, 5, 8; combined administration of 5-AZA-CdR and mAb 9H10
according to the above reported schedules, or saline solution for control. Tumor volumes from mice were measured periodically, all along the treatment. Mean tumor volumes for each group are reported. Vertical arrows indicate days of different treatments. *, p<0.05 vs. tumor volume of control group.
Figure 6. Immunohistochemical analysis of T cell infiltration by 5-AZA-CdR combined with mAb 9H10 in the syngeneic TS/A mouse tumor model. BALB/c mice were inoculated sc with 2x l05 TS/A cells. Groups of 5 mice were injected ip with 5-AZA-CdR 15 mg/kg (fractionated in three injections a day, every 3 h) on days 0, 7 combined with mAb 9H10 10(^g on days 2, 5, 8; or with saline solution for control. A week after the end of treatment, neoplastic tissues were excised and snap frozen in liquid nitrogen. Four micron acetone-fixed cryostat sections were processed for IHC assays. Representative results from 3 investigated mice are reported. A, B: CD4 and CD8 staining of tumors from mice treated with the combination of 5-AZA-CdR and mAb 9H10, respectively. Detailed description of the invention
Methods
Cells and animals
The murine mammary carcinoma TS/A cell line, established from a spontaneously originating malignancy 15 and displaying no significant transplant immunogenicity in syngeneic host, was grown in DMEM Medium (Biochrom AG, Cat # FG 0445) supplemented with 10% heat- inactivated fetal bovine serum (FBS) (Lonza, Cat # DEI 4-802), 2 mM L-glutamine (Biochrom AG, Cat # K 0282) and 50μΜ β-mercaptoethanol. The commercially available murine malignant mesothelioma AB1 cell 16 line was purchased from CellBank Australia (Cat # CBA- 0144) and grown in RPMI Medium (Biochrom AG, Cat # FG 1215) supplemented with 5% heat-inactivated FBS, and 2 mM L-glutamine .
Six-week-old female BALB/c, athymic nude and SCID/Beige mice were purchased from Harlan Laboratories. Animal care and experiments were in accordance with Institutional guidelines and the indications of Workman et al. 17
For colon carcinoma and Lewis lung carcinoma the lines are CT26.WT (ATCC® CRL- 2638™)) and 3LL (JCRB Cell Bank #JCRB1348), respectively.
Monoclonal antibodies and demethylating agents for in vivo treatment
The hamster mAb 9H10 against murine CTLA-4 was purchased from BioXCell (cat # BE0131). The isotype control ChromePure Syrian hamster IgG were purchased from Jackson
Immuno Research (cat # 007-000-003).
The rat mAb 10F.9G2 against murine PD-L1 (cat #BE0101), the hamster mAb J43 against murine PD-1 (cat #BE0033-2), the rat mAb C9B7W against murine LAG3 (cat # BE0174) were purchased from BioXCell.
5-AZA-CdR was purchased from Sigma Chemical Co. (cat # A3656).
Mice treatment
Mice were injected subcutaneously (sc) in the flank region with TS/A (2>< 105) (BALB/c, athymic nude and SCID/Beige) or ABl (3xl06) (BALB/c) cells resuspended in 0.1 ml of physiologic saline. Animals were examined daily and after a latency period of 1 week for TS/A and of 10 days for ABl, mice bearing clearly palpable and visible tumor grafts (diameter > 0.2 cm) were randomly grouped and treated intraperitoneally (ip) with 0.2 ml/injection of: i) 15 mg/kg of 5-AZA-CdR (fractionated in three injections a day, every three hours) on days 0 and 7 (1st cycle of treatment) and on days 42 and 49 (2nd cycle of treatment); ii) 100μg of hamster mAb 9H10, on days 2, 5 and 8 (1st cycle of treatment) and on days 44, 47 and 50 (2nd cycle of treatment); iii) combined administration of 5-AZA-CdR and mAb 9H10 according to the above reported schedules; iv) 100 μg of isotype control hamster IgG on days 2, 5 and 8; or v) combined administration of 5-AZA-CdR and hamster IgG according to the above reported schedules. Control mice were injected ip with 0.2 ml of saline solution. The rational choice of the dose/schedule of 5-AZA-CdR utilized for these experiments derived from preliminary experiments the inventors had performed in immunocompetent and immunocompromised mice (data not shown). The 15 mg/kg/day regimen had the best tumor immunomodulation with no/limited mice toxicity and was therefore chosen for the in vivo experiments..
Animals were monitored weekly for changes in tumor size and sacrificed by C02 overdose. Tumor and normal tissues were surgically removed, and each specimen, divided under sterile conditions, was snap-frozen in liquid nitrogen and stored at -80°C until used for RNA and DNA extraction or IHC assays.
In vivo anti-tumor activity and tolerability
Tumor size, evaluated by caliper measurements, and body weight were recorded periodically all along the treatment. Tumor volume were calculated as follows: tumor volume =LD2/2 (in which L and D are the longest and the shortest diameters, respectively). % of tumor growth inhibition was calculated using the formula: 100 - to™"°lmgcM6a mtCB:» , 100
tamer velum etcontrol micB)
In vivo tolerability was evaluated by measurements of body weight and mortality rate, as well as by periodic veterinary control. For the duration of treatment, veterinary inspection showed a good tolerability of the experimental therapies which was not associated with relevant changes in body weight (data not shown).
RNA and DNA extraction
RNA and DNA were extracted from tissues sections, removed from TS/A tumor of control and treated mice and homogenized with the aid of Tissue Lyser II (QIAGEN) in Trizol reagent (Invitrogen, cat # 15596-026) or lysis buffer, respectively. Total RNA was extracted following the manufacturer's instructions and stored at -80°C. Total genomic DNA was extracted by digestion with 100 μg/ml proteinase K in the presence of 0.5% SDS at 50°C overnight, followed by phenol/chloroform extraction and ethanol precipitation. Genomic DNA was dissolved in TE buffer and stored at -20°C. RT-PCR analysis
RT-PCR reactions were performed using oligonucleotide primer sequences and PCR amplification programs specific for PI A and Mage-a. 18'19 The integrity of RNA and random primers-synthesized cDNA was confirmed by the amplification of all cDNA samples with mouse ?-actm-specific primers, as previously described. 6 Five μΐ of each RT-PCR sample were run on a 2% agarose gel, stained with ethidium bromide and visualized by Gel doc XR (BioRad Laboratories).
Quantitative Methylation-Specific PCR analyses
Bisulfite conversion was carried out on 500 ng genomic DNA using EZ DNA Methylation- Gold™ Kit (Zymo Research, cat # D5005), according to the manufacturer's protocol. Primers for the analysis of the methylation status of PI A, designed using the free on-line software MethPrimer, 20 were: PI A (Methylated), forward 5'-
TTAAGTGCGTTATTACGTTTGGTTTTTAC-3' (SEQ ID No. 1), reverse 5'- ATAACCGATTATTTAATACAAAAATCGACG-3' (SEQ ID No. 2); PI A (Unmethylated), forward 5 '-GATTAAGTGTGTTATTATGTTTGGTTTTTAT-3 ' (SEQ ID No. 3), reverse 5'- ACATAACCAATTATTTAATACAAAAATCAACA-3 ' (SEQ ID No. 4). SYBR green quantitative Methylation-Specific PCR reactions were performed on 2 μΐ of bisulfite-modified genomic DNA in a final volume of 25 μΐ IX Power SYBR green mastermix (Applied Biosystems, cat # 4367659) at 95°C for 10 min, followed by 45 cycles of 15 sec at 95°C and 1
min at 60°C, using methylated- or unmethylated-specific primer pairs. The copy number of methylated or unmethylated sequences for the target gene was established in each sample by extrapolation from the standard curves. The percentage of methylation was defined as the ratio between methylated molecules and the sum of methylated and unmethylated molecules.
Immunohistochemical studies
One week after the end of treatment, TS/A tumors from 3 animals randomly selected from each experimental and control group, and normal tissues (lung, skeletal muscle, kidney, colon, ileum, hearth, liver, skin, brain cortex) from 2 animals from the same groups, were collected, immediately snap frozen in liquid nitrogen and kept at -80° C before further processing. Four micron non-consecutive cryostat sections were collected upon single tissue slides using the Leica CM 1850 cryostat. After air drying, sections were fixed 10 min. in absolute acetone and immediately assayed immunohistochemically or stored at -20°C with no loss of immune reactivity. The following antibodies were employed: polyclonal anti human CD3+ cross reacting with murine T lymphocytes (Dako, cat # A045201), anti mouse MHC class I mAb 28- 14-8S anti H2Db (ATCC HB-27) 21 and AF6-88.5.3 anti H2Kb (ATCC HB-158). 22 Rat anti mouse CD4 (Clone H129.19 cat # 550278) and CD8a (Clone 53-6-7 cat # 563332) lymphocytes were purchased from BD Bioscience. Primary antibodies dilutions were established using normal mouse spleen sections. Samples incubated with isotype matched immunoglobulins were used as negative controls. Reactivity of murine antibodies was assessed using the Vector Labor immunoenzymatic MOM Kit employing AEC as chromogenic substrate. The reactivity of non murine primary antibodies was established using an biotin labelled secondary antibodies and Vectastain immunoenzymatic kit and AEC as enzymatic substrate. Nuclear counterstain was done with Mayer's hematoxylin. To assure a comprehensive analysis, number of CD3+, CD4+ and CD 8+ lymphocytes was counted in at least 3 non-consecutive sections of the same tumor, on at least 5 randomly selected microscopic fields at 160, 200 and 250 x magnification. Tumor areas with extensive necrosis were excluded from this analysis. The counts were independently done blindly by two investigators and average values are reported. Statistical analysis
Data analyzed by Student's unpaired T test with p<0.05 were considered statistically significant.
Results
Effect of 5-AZA-CdR combined with mAb 9H10 on tumor growth
The anti-tumor activity of 5-AZA-CdR combined with the anti-CTLA-4 mAb 9H10, as compared to monotherapy, was investigated in BALB/c mice grafted with the poorly immunogenic TS/A breast carcinoma cells (#5 mice/group). Representative data from three independent experiments are shown in Figure 1.
At day 12 from the beginning of treatment a 67% (p<0.001), 44% (p<0.01) and 24% (p=0.41) reduction in tumor volumes was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA- CdR, and mAb 9H10, respectively, as compared to control mice (Fig. 1). The inhibition in tumor growth observed early in the course of treatment with both 5-AZA-CdR-based therapies persisted at day 41, being 77% (mean tumor volume = 0.86 ± 0.31 cm3) (p<0.01) and 54% (mean tumor volume = 1.8 ± 0.38 cm3) (p<0.01) for the combination and for 5-AZA-CdR alone, respectively (Fig. 1). On the other hand, the reduction (33%) in tumor volumes, obtained at day 41, from mice treated with mAb 9H10 alone (mean tumor volume = 2.59 ± 1.93 cm3) as compared to control mice (mean tumor volume = 3.87 ± 0.74 cm3) remained not significant; furthermore, these two sets of mice had to be euthanized as the tumor volumes exceeded the maximum allowed standards (Fig. 1). Control hamster IgG administered alone or combined with 5-AZA-CdR did not affect tumor growth over the whole treatment course (data not shown).
To evaluate the cumulative anti-tumor activity of repeated administrations of combination therapy, surviving mice received a 2nd cycle of 5-AZA-CdR combined with mAb 9H10 or 5- AZA-CdR alone at day 42 (Fig. 1). At day 50 the tumor volume was significantly (p<0.01) lower in mice receiving the combination (5 out of 5) (mean tumor volume = 1.07 ± 0.43 cm3) as compared to 5-AZA-CdR alone (4 out of 5) (mean tumor volume = 2.36 ± 0.32 cm3) (Fig. 1); this difference persisted until day 57 when animals from the 5-AZA-CdR monotherapy-treated group (3 out of 5) had to be euthanized due to tumor volume (data not shown).
A strong anti-tumor activity of this combination regimen was also found using a model of malignant mesothelioma, mice grafted with syngeneic AB1 mesothelioma cells (#3 mice/group). In detail, a 81% (p<0.05) and 33% (p=0.10) reduction in tumor volumes was observed at day 20 of treatment with 5-AZA-CdR in combination with mAb 9H10 and 5-AZA- CdR alone, respectively, as compared to control mice. No reduction in tumor volumes was observed in mice treated with mAb 9H10 alone, as compared to control mice (Fig. 5).
Immunomodulatory activity of 5-AZA-CdR combined with mAb 9H10 on TS/A tumors
The immunomodulatory activity of 5-AZA-CdR combined with mAb 9H10 was investigated in TS/A tumors excised one week after the end of treatment from 3 randomly selected treated and control mice; changes in the expression of different murine Cancer Testis Antigen (i.e., tumor rejection antigen PI A (PI A) and Melanoma Antigen A (Mage-a) family members) and of MHC class I antigens were utilized as readouts.
RT-PCR unveiled a de novo expression of PI A and Mage-a members in neoplastic tissues from animals treated with 5-AZA-CdR alone or combined with mAb 9H10; in contrast, no effect was observed following treatment with the anti-CTLA-4 mAb alone (Fig. 2A).
Consistent with the direct involvement of DNA methylation in the regulation of Cancer Testis Antigen expression, quantitative Methylation-Specific PCR analysis identified a significant (p<0.05) reduction of P1A promoter methylation in tumor tissues from mice treated with 5- AZA-CdR alone or combined with mAb 9H10, as compared to control mice (Fig. 2B). No reduction in the methylation of PI A promoter was observed in tumors from mice treated with the mAb 9H10 alone (Fig. 2B).
Representative results of the immunohistochemical analysis for the expression of MHC class I antigens reported in Figure 3 demonstrate a weak and heterogeneous expression, with intermingled negative and weakly positive areas, of MHC class I molecules in control (Fig. 3 A), mAb 9H10 (Fig. 3B), and hamster IgG (data not shown) treated mice; in contrast, a stronger and more homogeneous expression of MHC class I antigens was detected in tumors from mice treated with 5-AZA-CdR alone (Fig. 3C) or combined with hamster IgG (data not shown). The extensive necrosis of tumors from mice treated with 5-AZA-CdR combined with mAb 9H10 allowed a conclusive interpretation on the changes of MHC class I antigens expression only in two animals (data not shown). Anti-tumor activity of 5-AZA-CdR combined with mAb 9H10 in immunodeficient mice
To investigate the contribution of host's immune response in mediating the anti-tumor effect observed in BALB/c mice, the therapeutic combination of 5-AZA-CdR and mAb 9H10 was also explored in T cell-deficient athymic nude mice and in Τ-cell-, B-cell- and NK cell- deficient SCID/Beige mice grafted with TS/A cells. Groups of 4 mice for each strain, were injected ip with 5-AZA-CdR, mAb 9H10, the combined administration of 5-AZA-CdR and mAb 9H10, or with saline solution for control. Treatment with mAb 9H10 did not affect tumor growth in either immunodeficient models investigated (Fig. 4A, B). 5-AZA-CdR reduced tumor growth in both animal models (Fig 4A, B); noteworthy, no further reduction in tumor growth was detected when mAb 9H10 was added to 5-AZA-CdR monotherapy in both athymic nude
mice (Fig. 4A) and SCID/Beige immunocompromised mice (Fig. 4B). Treatment of immunocompetent BALB/c mice, utilized as internal controls, led to results similar to those previously obtained (data not shown). Analysis of immune cell infiltrates in neoplastic and normal tissues
To characterize the relative contribution of the T cell compartment in mediating the anti-tumor activity of 5-AZA-CdR combined with mAb 9H10, TS/A tumor tissues, randomly selected from 3 out of 5 treated and control mice, were evaluated for T cells infiltration.
Tumors from control animals displayed no necrosis and no infiltration by CD3+ lymphocytes (Fig. 3D). In contrast, treatment with 5-AZA-CdR or with mAb 9H10 resulted in tumors with an average of 30% of necrosis and a CD3+ infiltrate of 15.2 (+/- 0.5) (data not shown), or with variable areas of necrosis and CD3+ lymphocytes infiltrate of 27 (+/- 1.7) (Fig. 3E) with a balanced presence of CD4+ and CD 8+ cells, respectively. Treatment with 5-AZA-CdR combined with mAb 9H10 generated extensive areas of necrosis, loss of tissue architecture and the highest number of tumor infiltrating CD3+ lymphocytes (more than 40 CD3+ cells) (Fig. 3F). Also in this instance a balanced presence of CD4+ and CD8+ cells was observed (Fig. 6). Number of T-cell infiltrates are summarized in Table 1.
Table 1. Count of T cell infiltrates in neoplastic tissues from control and treated mice grafted with TS/A cells.
CD3 CD4 CD8
Cell Cell Cell
# micea Treatment numberb SD numberb SD numberb SD
3 Control 4.8C 1.7 ndd - nde
2 IgG 7.8 4.2 nd - nd
3 mAb 9H10 27.2 0.2 30 2.8 27.3 2.5
3 5-AZA-CdR 15.2 0.25 nd - nd
3 5-AZA-CdR + IgG 22.8 2.2 nd - nd
3 5-AZA-CdR + mAb 9H10 >40 balanced number of CD4 and CD8 a, number of investigated mice; b, counts were independently done blindly by two investigators at 160x magnification and average values are reported; c, average number of CD3-positive cells; d, average number of CD4-positive cells; e, average number of CD8-positive cells; nd, not done
In contrast to tumor tissues, staining for CD3+ lymphocytes showed only isolated T cells in normal colon, ileum, skin, liver, kidney, brain, hearth, muscle and lung of 2 randomly selected mice with no differences between control and treated mice in terms of number and localization (Fig. 3G, N and data not shown).
Discussion
The notion that epigenetically-driven events can down-regulate the immunogenicity and immune recognition of neoplastic cells, and that DNA hypomethylating agents can efficiently revert this phenomenon, 2 led the inventors to hypothesize that combining such compounds with emerging immunotherapeutic agents, such as immune check-point blocking mAb, could result in potentially more effective anti-cancer strategies. This working hypothesis is now supported by the experimental data of the present invention that demonstrated an immune- mediated, anti-tumor activity of 5-AZA-CdR combined with the anti-CTLA-4 mAb 9H10. The anti-tumor efficacy of DNA hypomethylating agents combined with CTLA-4 blockade that the inventors observed is relevant from the translational standpoint also in view of the well- known limited activity of anti-CTLA-4 mAb utilized as single agents in poorly immunogenic mouse models, 23'24'25'26 which was confirmed also with the TS/A model utilized in this study. From a prospective clinical development these findings seem to imply that DNA hypomethylating agents in combination with CTLA-4 blockade could be efficiently utilized to improve the effectiveness of anti-CTLA-4 mAb also in poorly immunogenic human malignancies. Furthermore, the findings of the present study demonstrate that the efficacy of this novel combination becomes appreciable at early treatment time-points. Translating this finding into the clinics of anti-CTLA-4 therapy is of particular relevance to counteract the late- in-onset anti-tumor activity of CTLA-4 blocking mAb in cancer patients, 27'28 .
The inventors have recently demonstrated that epigenetic remodeling of TS/A tumors by 5- AZA-CdR preferentially modulated gene expression profiles belonging to immune-related pathways, 6 suggesting for a broad spectrum of immune genes and mechanisms that could contribute to improve the immunogenicity and immune-recognition of DNA hypomethylating agents -treated cancer cells. Confirming this activity of 5-AZA-CdR, in the present invention the expression of the methylation-regulated PI A gene was up-regulated exclusively in 5-AZA- CdR-containing regimens. Additional support to the broad functional immunomodulation of neoplastic cells by DNA hypomethylating agents derives from the immunohistochemical finding that the expression of MHC class I molecules was up-regulated in 5-AZA-CdR-treated tumors. This observation is particularly appealing in view of the demonstration that the up-
regulation of HLA class I antigens induced by 5 -AZA-CdR was per se sufficient to improve gplOO-specific cytotoxic T cell recognition of melanoma cells. 5 In addition, loss of expression of HLA class I molecules by tumor cells has been recently suggested to represent a mechanism of tumor resistance that can develop during CTLA-4 therapy with ipilimumab. 29 Therefore, the up-regulation of HLA class I molecules induced by DNA hypomethylating agents in vivo could contribute to: i) improve immune-recognition of neoplastic cells; ii) recover the efficacy of CTLA-4 blockade in patients progressing to treatment due to down-regulation of HLA class I molecules on tumor cells. Even though these evidence do not allow to restrict the anti-tumor activity of the combined regimen to the up-regulated MHC class I and tumor antigen expression on neoplastic cells, the involvement of immune effector mechanism(s) in the anti-tumor activity of the combination regimen observed in immunocompetent mice is strongly underlined by the overlapping patterns of tumor growth observed in immune-compromised mice treated with 5- AZA-CdR alone or combined with mAb 9H10. The potential contribution of T cell immunity in the therapeutic effectiveness of the combination regimen investigated in this study is further supported by the highest degree of CD3+ infiltrating cells identified in TS/A tumors from mice treated with 5-AZA-CdR and mAb 9H10. Consistent with previous observations demonstrating that tumor-specific immune responses induced by immune checkpoint blockade depend on both CD4+ and CD8+ T cells, 30'31 the lymphocyte tumor infiltration comprised both CD4+ and CD8+ T cells.
Opposite to tumor tissues, only isolated T cells were detected in different organs from treated and control mice. This finding might bear a significant practical relevance for the clinical use of the combined regimen. Potentially fatal immune-related adverse effects (irAEs), associated with heavy lymphocytic infiltration in normal organs, have been extensively documented in patients treated with CTLA-4-b locking mAb. 32'33 Therefore, although the weaknesses of the preclinical model at detecting irAEs for the resistance of the mice strain used in developing irAEs, 34 it can be envisaged that these auto-reactive phenomena will be likely not be worsened by the combination therapy. Along this very same line are inventors' previous data reporting comprehensively limited effect(s) of DNA hypomethylating agents on gene expression profiles of normal tissues in mice. 6
A strong anti-tumor activity was achieved with DNA hypomethylating agents combined with immunomodulating antibodies for instance CTLA-4-blocking antobodies utilizing the AB1 mesothelioma ,in spite of its high in vivo aggressiveness. As a matter of facts, it was necessary to euthanize control and mAb 9H10-treated mice at day 21. The efficacy of the combined
treatment in this model demonstrates that its anti-tumor activity represents a general phenomenon occurring regardless of tumor histotype.
Overall, the findings of the present invention provide a sound scientific rationale to translate the immunomodulatory activities of epigenetic drugs into the clinic, for novel and potentially more effective combinatorial immunotherapeutic strategies with immunomodulating antibodies such as anti-CTLA-4, anti-PD-1 and/or anti-PDL-1 mAb.
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Claims
1. A DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent for use in the treatment and/or in the prevention of malignant mesothelioma.
2. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 1 wherein the DNA hypomethylatmg agent is selected from the group consisting of: 5-azacytidine, 5- aza-2'-deoxycytidine (5-AZA-CdR), zebularine, procainamide, procaine, hydralazine, epigallocathechin-3-gallate, RG108, MG98.
3. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 1 or 2 wherein the immunomodulatory agent is selected from the group consisting of: immunomodulating antibody, cancer vaccine, therapeutic cytokine, cellular therapy.
4. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 3 wherein the immunomodulating antibody is selected from the group consisting of: an anti-CTLA-4, an anti-PDL-1, an anti-PDL-2, an anti-PDl, an anti-CD137, an anti-CD40, anti-LAG3, anti-TIM3, anti-KIR, anti-GITR, anti-ICOS or an anti-OX-40 antibody.
5. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 3 wherein the cancer vaccine is selected from the group consisting of: anti-idiotypic antibodies, inhibitors of angiogenesis, Tumor Antigen specific peptides or recombinant proteins.
6. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 3 wherein the therapeutic cytokine is selected from the group consisting of: GM-CSF, IL-2, IL-12, IL- 17, TNF a, IFN y or IFN a.
7. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 3 wherein the cellular therapy is selected from the group consisting of: T cells, stem cells, dendritic cells, gene- or pharmacologically-modified immune and/or cancer cells.
8. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to any one of previous claim wherein the targeted therapy agent is selected from the group consisting of: a
MAP kinase pathway inhibitor, IDO inhibitor, JAK inhibitor or a WNT pathway inhibitor.
9. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or the least one targeted therapy agent for use according to claim 8 wherein the MAP kinase pathway inhibitor is selected from the group consisting of : a BRAF inhibitor, a
MEK inhibitor, a PI3K inhibitor or a c-KIT inhibitor.
10. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 9 wherein the BRAF inhibitor is selected from the group consisting of: GDC-0879, PLX-4720, Sorafenib Tosylate, dabrafenib or LGX818.
11. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 9 wherein the MEK inhibitor is selected from the group consisting in: GSK1120212, selumetinib or MEK162.
12. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or the least one targeted therapy agent for use according to claim 8 wherein the WNT pathway inhibitor is selected from the group consisting of: a beta catenin inhibitor or a frizzled inhibitor.
13. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to claim 12 wherein the beta catenin inhibitor is selected from the group consisting of: niclosamide, XAV-939, FH 535 or ICG 001.
14. The DNA hypomethylatmg agent and the at least one immunomodulatory agent for use according to any one of previous claim wherein the DNA hypomethylatmg agent is 5- AZA-CdR and the immunomodulating antibody is an anti-CTLA-4 and/or an anti-PDL-
1 antibody.
15. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to any one of previous claim wherein the malignant mesothelioma is resistant or refractory to at least one anti- tumor therapy.
16. The DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the least one targeted therapy agent for use according to any one of previous claim wherein the DNA hypomethylatmg agent and at least one immunomodulatory
agent and/or optionally the least one targeted therapy agent are administered simultaneously or sequentially.
17. A pharmaceutical composition comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined in any one of claims 1 to 14 for use in the treatment and/or in the prevention of malignant mesothelioma.
18. The pharmaceutical composition for use according to claim 17 further comprising an anti-tumoral agent.
19. A kit comprising a DNA hypomethylatmg agent and at least one immunomodulatory agent and/or optionally at least one targeted therapy agent as defined in any one of claims 1 to 14 for use in the treatment and/or in the prevention of malignant mesothelioma.
20. The kit for use according to claim 19 wherein the DNA hypomethylatmg agent and the at least one immunomodulatory agent and/or optionally the at least one targeted therapy agent are in separated containers.
21. A method of treating and/or preventing malignant mesothelioma comprising administering an effective amount of a DNA hypomethylatmg agent and an effective amount of at least one immunomodulatory agent and/or optionally an effective amount of at least one targeted therapy agent.
22. The method according to claim 21 wherein the DNA hypomethylatmg agent is 5-AZA- CdR and the immunomodulatory agent is an anti-CTLA-4 and/or an anti-PDL-1 and/or an anti-PD-1 antibody.
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