Combination of oncolytic virus with immune checkpoint modulators

1. A method for treating a cancer, comprising administering:

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 is defective for Ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral I4L and/or F4L gene(s) and

ii) one or more immune checkpoint modulator(s) consisting of an antibody, wherein the antibody specifically binds to PD-1 and is selected from Nivolumab and Pembrolizumab,

wherein said cancer is selected from the group consisting of: bone cancer, liver cancer, pancreatic cancer, stomach cancer, colon cancer, cancer of the esophagus, oro-pharyngeal cancer, lung cancer, cancer of the head or neck, skin cancer, melanoma, uterine cancer, cervix cancer, ovarian cancer, breast cancer, rectal cancer, cancer of the anal region, prostate cancer, lymphoma, cancer of the endocrine system, cancer of the thyroid gland, sarcoma of soft tissue, chronic or acute leukemias, cancer of the bladder, renal cancer, neoplasm of the central nervous system (CNS), and glioma,

wherein said oncolytic vaccinia virus and said one or more immune checkpoint modulator(s) are administered sequentially and

wherein said oncolytic vaccinia virus is administered first and said immune checkpoint modulator(s) is administered second.

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 selected from the group consisting of genes encoding suicide gene products and genes encoding immunostimulatory proteins.

3. The method of claim 2 , wherein said suicide gene is selected from the group consisting of genes 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 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 oncolytic vaccinia virus is defective for both TK and RR activities and comprising inserted into its genome the therapeutic 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 6 , wherein said oncolytic vaccinia virus is defective for TK activity and comprises inserted into its genome the therapeutic human GM-CSF.

8. The method according to claim 1 comprising from approximately 10 7 pfu to approximately 5×10 9 pfu of said oncolytic vaccinia virus.

9. The method of claim 1 , comprising from about 2 mg/kg to about 15 mg/kg of said one or more immune checkpoint modulator(s).

10. The method of claim 1 , wherein said immune checkpoint modulator(s) is administered by intravenous, intratumoral or intraperitoneal route and wherein said oncolytic vaccinia virus is administered by intravenous or intratumoral route.

11. The method of claim 1 , which comprises from 2 to 5 intravenous or intratumoral administrations of 10 8 or 10 9 pfu of oncolytic vaccinia virus at approximately 1 or 2 weeks interval followed by or interspersed with 2 to 5 intravenous administrations of 3 to 10 mg/kg of one or more anti-immune checkpoint antibody(ies)(s) every 2 or 3 weeks.

12. A kit comprising:

i) in one container 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 is defective for Ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral 14L and/or F4L gene(s);

ii) in another container one or more immune checkpoint modulator(s) consisting of an antibody, wherein the antibody specifically binds to PD-1 and is selected from Nivolumab and Pembrolizumab; and

iii) instructions for use indicating that said oncolytic vaccinia virus and said one or more immune checkpoint modulator(s) are to be administered sequentially and that said oncolytic vaccinia virus is to be administered first and said immune checkpoint modulator(s) is to be administered second.

13. A pharmaceutical composition comprising:

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 is defective for Ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral 14L and/or F4L gene(s); and

ii) one or more immune checkpoint modulator(s) consisting of an antibody, wherein the antibody specifically binds to PD-1 and is selected from Nivolumab and Pembrolizumab.

14. A method for treating a cancer, comprising administering:

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 is defective for Ribonucleotide reductase (RR) activity resulting from inactivating mutations in the viral I4L and/or F4L gene(s), and wherein said oncolytic vaccinia virus is approximately 10 7 pfu to approximately 5×10 9 pfu; and

ii) an antibody selected from Nivolumab and Pembrolizumab, wherein said antibody is about 1 mg/kg to about 20 mg/kg;

wherein said cancer is selected from the group consisting of: bone cancer, liver cancer, pancreatic cancer, stomach cancer, colon cancer, cancer of the esophagus, oro-pharyngeal cancer, lung cancer, cancer of the head or neck, skin cancer, melanoma, uterine cancer, cervix cancer, ovarian cancer, breast cancer, rectal cancer, cancer of the anal region, prostate cancer, lymphoma, cancer of the endocrine system, cancer of the thyroid gland, sarcoma of soft tissue, chronic or acute leukemias, cancer of the bladder, renal cancer, neoplasm of the central nervous system (CNS), and glioma;

wherein said oncolytic vaccinia virus and said antibody are administered sequentially; and

wherein said oncolytic vaccinia virus is administered first and said antibody is administered second.