Granted Patent B2

US 12,622,937 · App. 16/985,607 · Granted May 12, 2026

Inventors: Laurence Zitvogel (Paris, FR); Xavier Preville (Saint Louis, FR); Laetitia Fend (Le Kremlin-bicetre, FR)

Assignees: Institut Gustave-Roussy; Transgene SA

A61K35/768A61K9/0019A61K35/28A61K38/193A61K39/00A61K39/3955C07K16/2818C07K16/2827C12N5/00C12N7/00A61K2039/505C07K2317/76C12N2710/24132

Abstract

Claims (20)

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 . 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 . 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 . The method of claim 3 , wherein said suicide gene product has CDase and UPRTase activities.

5 . The method of claim 4 , wherein said suicide gene is FCU1 suicide gene.

6 . The method of claim 2 , wherein said immunostimulatory protein is an interleukin or a colony-stimulating factor.

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 . 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 . 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 . 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 . 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 . 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.

Priority Claims (1)

Continuity (2)

References Cited (176)