US-12622937-B2 - Combination of oncolytic virus with immune checkpoint modulators

Abstract

The present invention provides a combination comprising at least an oncolytic virus and one or more immune check-point modulator(s) for use for the treatment of a proliferative disease such as cancer. It also relates to a kit comprising said oncolytic virus and said one or more immune checkpoint modulator(s) in separate containers. It also concerns a pharmaceutical composition comprising effective amount of said oncolytic virus and said one or more immune checkpoint modulator(s).

Inventors

• Laurence Zitvogel
• Xavier Preville
• Laetitia Fend

Assignees

• INSTITUT GUSTAVE-ROUSSY
• TRANSGENE SA

Dates

Publication Date

20260512

Application Date

20200805

Priority Date

20140716

Claims (12)

1. 1 . A method of therapy in a human subject diagnosed with cancer, comprising administering to the human subject: i) an oncolytic vaccinia virus, wherein said oncolytic vaccinia virus is defective for thymidine kinase (TK) resulting from inactivating mutations in the J2R viral gene and defective for ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral 14L and/or F4L gene(s); and ii) a monoclonal antibody that specifically binds to CTLA-4 that is ipilimumab or tremelimumab; wherein i) and ii) are administered sequentially and i) is administered first and ii) second; wherein said oncolytic vaccinia virus is administered at a dose of 10 7 pfu to 5×10 9 pfu; and wherein said monoclonal antibody that specifically binds to CTLA-4 is administered at a dose of 2 mg/kg to 15 mg/kg.
2. 2 . The method of claim 1 , wherein said oncolytic vaccinia virus further expresses at least one therapeutic gene inserted in the viral genome, wherein said therapeutic gene is a gene encoding a suicide gene product or a gene encoding an immunostimulatory protein.
3. 3 . The method of claim 2 , wherein said suicide gene is a gene encoding a protein having a cytosine deaminase (CDase) activity, a thymidine kinase activity, an uracil phosphoribosyl transferase (UPRTase) activity, a purine nucleoside phosphorylase activity, and/or a thymidylate kinase activity.
4. 4 . The method of claim 3 , wherein said suicide gene product has CDase and UPRTase activities.
5. 5 . The method of claim 4 , wherein said suicide gene is FCU1 suicide gene.
6. 6 . The method of claim 2 , wherein said immunostimulatory protein is an interleukin or a colony-stimulating factor.
7. 7 . The method of claim 1 , wherein said ipilimumab or tremelimumab is administered by intravenous, intratumoral or intraperitoneal route and wherein said oncolytic vaccinia virus is administered by intravenous or intratumoral route.
8. 8 . The method of claim 1 , which comprises from 2 to 5 intravenous or intratumoral administrations of 10 8 or 10 9 pfu of said oncolytic vaccinia virus at approximately 1 or 2 weeks interval followed by or interspersed with 2 to 5 intravenous administrations of 3 mg/kg to 10 mg/kg of said ipilimumab or tremelimumab every 2 or 3 weeks.
9. 9 . The method of claim 1 , wherein said cancer is selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and liver cancer.
10. 10 . A kit comprising: i) an oncolytic vaccinia virus in one container, wherein said oncolytic vaccinia virus is defective for thymidine kinase (TK) resulting from inactivating mutations in the J2R viral gene and defective for ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral 14L and/or F4L gene(s); and ii) a monoclonal antibody that specifically binds to CTLA-4 that is ipilimumab or tremelimumab in another container, wherein i) are intended for sequential administration, i) being administered first at a dose of 10 7 pfu to 5×10 9 pfu and ii) second at a dose of 2 mg/kg to 15 mg/kg.
11. 11 . The method of claim 1 , wherein the monoclonal antibody that specifically binds to CTLA-4 antagonizes more than 50% of the activity of CTLA-4.
12. 12 . The kit of claim 10 , wherein the monoclonal antibody that specifically binds to CTLA-4 antagonizes more than 50% of the activity of CTLA-4.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation Application of U.S. patent application Ser. No. 15/325,576, filed on Jan. 11, 2017, which is a U.S. National Stage Application pursuant to 35 U.S.C. § 371 of International Patent Application PCT/EP2015/066353, filed on Jul. 16, 2015, and published as WO 2016/009017 on Jan. 21, 2016, which claims priority to European Patent Application 14306155.4, filed on Jul. 16, 2014, all of which are incorporated herein by reference in their entireties for all purposes. JOINT RESEARCH AGREEMENT The subject matter of this application was developed and the claimed invention was made by or on behalf of one or more of TRANSGENE SA and INSTITUT GUSTAVE-ROUSSY pursuant to a joint research agreement within the meaning of 35 U.S.C. § 100 (h) and 37 C.F.R. § 1.9 (e) that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement. FIELD OF THE INVENTION The present invention generally relates to the field of oncolytic virotherapy and more specifically to compositions and methods to treat, prevent, or inhibit proliferative diseases, especially cancer. Embodiments include an oncolytic virus for use for the treatment of cancer in combination with one or more immune checkpoint modulator(s). Embodiments also include a kit comprising such components and method of treatment using said oncolytic virus with said one or more immune checkpoint modulator(s). Each year, cancer is diagnosed in more than 12 million subjects worldwide. In industrialized countries, approximately one person out five will die of cancer. Although a vast number of chemotherapeutics exist, they are often ineffective, especially against malignant and metastatic tumors that establish at a very early stage of the disease. Moreover, antitumor immunity is often ineffective due to the fact that tumor cells have evolved mechanisms to escape host defense. One of the major mechanisms of immune suppression is a process known as “T-cell exhaustion”, which results from chronic exposure to antigens and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions. Various immune checkpoints acting at different levels of T cell immunity have been described in the literature, including programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2, CTLA-4 (cytotoxic T-lymphocyte associated protein-4), LAG3 (Lymphocyte-activation gene 3), B and T lymphocyte attenuator, T-cell immunoglobulin, mucin domain-containing protein 3 (TIM-3), and V-domain immunoglobulin suppressor of T cell activation. Whatever the mechanism of action, these immune checkpoints can inhibit the development of an efficient anti-tumor immune response. There is increasing interest in the possible therapeutic benefits of blocking such immune checkpoints as a means of inhibiting immune system tolerance to tumors and thus rescue exhausted antitumor T cells (Leach et al., 1996, Science 271:1734-6). A vast number of antagonistic antibodies have been developed during the last decade (e.g. anti Tim3, -PD-L1, -CTLA-4, -PD1, etc) and most importantly, some have been associated with objective clinical responses in cancer patients. Antibodies targeting CTLA-4 are already marketed (e.g. Ipilimumab, YERVOY®, Bristol-Myers Squibb, BMS) for metastatic melanoma. BMS reported that from 1800 melanoma patients treated with ipilimumab 22% are still alive 3 years later. Antibody therapies with anti PD-L1 (e.g. MPDL3280A, Roche), anti PD-1 (e.g. Nivolumab, BMS) are also ongoing. Another therapeutic approach that is emerging in the field of cancer is oncolytic viruses (Hermiston, 2006, Curr. Opin. Mol. Ther. 8:322-30). Oncolytic viruses are capable of selective replication in dividing cells (e.g. cancer cell) while leaving non dividing cells (e.g. normal cells) unharmed. As the infected dividing cells are destroyed by lysis, they release new infectious virus particles to infect the surrounding dividing cells. Cancer cells are ideal hosts for many viruses because they have the antiviral interferon pathway inactivated or have mutated tumour suppressor genes that enable viral replication to proceed unhindered (Chernajovsky et al., 2006, British Med. J. 332:170-2). A number of viruses including adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia have now been clinically tested as oncolytic agents. Some viruses are naturally oncolytic (such as reovirus and the Seneca valley picornavirus) while others are engineered for tumor selectivity by modifying the viral genome. Such modifications include functional deletions in essential viral genes, the use of tumor- or tissue-specific promoters to control the viral gene expression and tropism modification to redirect virus to the cancer cell surfa