Combination of oncolytic virus with immune checkpoint modulators

• US 10,765,710 B2
• Filed: 07/16/2015
• Issued: 09/08/2020
• Est. Priority Date: 07/16/2014
• Status: Active Grant

• Current Assignee: Transgene S.A. (Compagnie Merieux Alliance SAS), Institut Gustave Roussy
• Original Assignee: Institut Gustave Roussy
• Inventors: Zitvogel, Laurence, Preville, Xavier, Fend, Laetitia
• Primary Examiner(s): Bristol, Lynn A
• Application Number:
  US15/325,576
• Publication Number:
  US 20170143780A1
• Time in Patent Office: 1,881 Days
• Field of Search: 4241331, 4241781
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/28 Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: 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
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C12N 2710/24132 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: 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
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

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

Claims

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 10⁷ pfu to approximately 5×

10⁹ 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 10⁸ or 10⁹ 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 10⁷ pfu to approximately 5×

10⁹ 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.