# US 12,622,937 B2 · Combination of oncolytic virus with immune checkpoint modulators > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,622,937 B2 - Document ID: US12622937B2 - Status: Granted - Kind: B2 - Application number: 16/985,607 - Filed: 2020-08-05 - Published: 2020-12-03 - Granted: 2026-05-12 - Earliest claimed: 2014-07-16 - Assignees: Institut Gustave Roussy; Transgene S.A. - Applicants: Institut Gustave-Roussy; Transgene SA - Inventors: Laurence Zitvogel; Xavier Preville; Laetitia Fend - Web page: https://patentgrep.com/patent/US12622937B2 ## CPC - A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766 - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells - A61K 38/193: {Colony stimulating factors [CSF]} - A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53) - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61P 35/00: Antineoplastic agents - C07K 16/2818: {against CD28 or CD152} - C07K 16/2827: {against B7 molecules, e.g. CD80, CD86} - C12N 5/00: Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor; (plant reproduction by tissue culture techniques A01H4/00) - C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) - A61K 2039/505: {comprising antibodies} - A61K 2039/5256: {expressing foreign proteins} - A61K 2039/545: {characterised by the dose, timing or administration schedule} - A61K 2039/585: {wherein the target is cancer} - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C12N 2710/24132: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) ## 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). ## Claims ### Claim 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 107 pfu to 5×109 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 2) 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. ### Claim 4 (depends on 3) The method of claim 3, wherein said suicide gene product has CDase and UPRTase activities. ### Claim 5 (depends on 4) The method of claim 4, wherein said suicide gene is FCU1 suicide gene. ### Claim 6 (depends on 2) The method of claim 2, wherein said immunostimulatory protein is an interleukin or a colony-stimulating factor. ### Claim 7 (depends on 1) 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. ### Claim 8 (depends on 1) The method of claim 1, which comprises from 2 to 5 intravenous or intratumoral administrations of 108 or 109 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. ### Claim 9 (depends on 1) 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. ### Claim 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 107 pfu to 5×109 pfu and ii) second at a dose of 2 mg/kg to 15 mg/kg. ### Claim 11 (depends on 1) 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. ### Claim 12 (depends on 10) 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.