# US 10,765,710 B2 · Combination of oncolytic virus with immune checkpoint modulators

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- Number: US 10,765,710 B2
- Document ID: US10765710B2
- Status: Granted
- Kind: B2
- Application number: 15/325,576
- Filed: 2015-07-16
- Published: 2017-05-25
- Granted: 2020-09-08
- 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/US10765710B2

## 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 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

### Claim 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.

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

### Claim 3 (depends on 2)

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.

### 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 oncolytic vaccinia virus is defective for both TK and RR activities and comprising inserted into its genome the therapeutic 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 6)

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.

### Claim 8 (depends on 1)

The method according to claim 1 comprising from approximately 107 pfu to approximately 5×109 pfu of said oncolytic vaccinia virus.

### Claim 9 (depends on 1)

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).

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 1)

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.

### Claim 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.

### Claim 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.

### Claim 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.