Immuno-Oncolytic Therapies

• US 20160235793A1
• Filed: 02/19/2016
• Published: 08/18/2016
• Est. Priority Date: 08/22/2013
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Thorne, Stephen Howard
• Granted Patent: US 11,478,518 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 2039/575 humoral response
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C12N 2710/24121 Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2710/24122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2710/24132 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/24134 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/24171 Demonstrated in vivo effect
• 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 relates to oncolytic vaccinia viruses which have been modified to promote anti-tumor immunity and/or reduce host immunity and/or antibody response against the virus. It is based, at least in part, on the discovery that oncolytic vaccinia virus (i) bearing a genome deletion of a gene that reduces T cell immunity (interleukin-18 binding protein); (ii) treated with a sialidase enzyme which is believed to reduce TLR2 activation and therefore the antibody response; (iii) carrying a gene that enhances cytotoxic T lymphocyte induction (e.g., TRIF) and/or (iv) reduces tumor myeloid-derived suppressor cells by reducing prostaglandin E2 reduces tumor growth. Accordingly, the present invention provides for immunooncolytic vaccinia viruses and methods of using them in the treatment of cancers.

Claims

1. An oncolytic vaccinia virus comprising two or more of the following modifications:

(i) a viral backbone mutation;

(ii) a modification of viral glycosylation;

(iii) a modification that promotes T cell response;

(iv) a modification that inhibits immunosuppression; and

/or

(v) a modification that enhances virus spread and activity.

5. The oncolytic vaccinia virus of claim 1, wherein the viral backbone mutation is a deletion or functional deletion of interleukin 18-binding protein.

6. The oncolytic vaccinia virus of claim 1, wherein the viral backbone mutation is a B8R deletion, a B18R deletion, an A35R deletion, or a combination thereof.

7. The oncolytic vaccinia virus of claim 1, wherein the modification that promotes T cell response is the incorporation of a nucleic acid encoding a Toll/IL-1R domain-containing adapter inducing interferon beta (TRIF) protein or a functional domain thereof.

8. The oncolytic vaccinia virus of claim 1, wherein the modification that promotes T cell response is the incorporation of a nucleic acid encoding granulocyte macrophage colony stimulating factor.

9. The oncolytic vaccinia virus of claim 1, wherein the modification that inhibits immunosuppression is the incorporation of a nucleic acid encoding a prostaglandin E2 antagonist.

10. The oncolytic vaccinia virus of claim 9, wherein the prostaglandin E2 antagonist is 15-PGDH.

11. The oncolytic vaccinia virus of claim 1, wherein the modification that enhances viral spread and activity is a modification that increases the amount of the extracellular enveloped form of the virus produced.

12. The oncolytic vaccinia virus of claim 11, wherein the modification is one or more of the following mutations:

A34R Lys151 to Glu;

complete or partial deletion of B5R;

mutation/deletion of A36R and/or mutation/deletion of A56R.

19. A method of reducing the growth of a cancer cell comprising administering, to the cancer cell, an effective amount of the oncolytic vaccinia virus of claim 1.

20. A method of reducing the growth of a tumor comprising administering, to the tumor, an effective amount of the oncolytic vaccinia virus of claim 1.

21. A method of treating a subject having a cancer comprising administering, to the subject, an effective amount of the oncolytic vaccinia virus of claim 1.

22. A method of producing an anti-cancer effect in a subject comprising administering, to the subject, an effective amount of the oncolytic vaccinia virus of claim 1.

23. The method of claim 21, further comprising administering one or more agents selected from the group consisting of an anti-cancer agent, an immunomodulatory agent, and a combination thereof.

2. An oncolytic vaccinia virus comprising a modification of viral glycosylation and one or more of the following modifications:

(i) a viral backbone mutation;

(ii) a modification that promotes T cell response;

(iii) a modification that inhibits immunosuppression; and

/or

(iv) a modification that enhances virus spread and activity.

3. An oncolytic vaccinia virus which is treated with an agent that reduces the amount of glycosylation prior to administration to a host or that otherwise has reduced glycosylation relative to unmodified virus.

4. An oncolytic vaccinia virus which is treated with an agent that reduces the amount of glycosylation prior to administration to a host or that otherwise has reduced glycosylation relative to unmodified virus and comprises one or more of the following modifications:

(i) a viral backbone mutation;

(ii) a modification that promotes T cell response;

(iii) a modification that inhibits immunosuppression; and

/or

(iv) a modification that enhances virus spread and activity.

13. An oncolytic vaccinia virus which is treated with an agent that reduces the amount of glycosylation prior to administration to a host or that otherwise has reduced glycosylation relative to unmodified virus, comprising, a nucleic acid encoding TRIF or a functional domain thereof and/or a nucleic acid encoding a PGE2 antagonist.

14. An oncolytic vaccinia virus comprising:

(i) a TK deletion;

(ii) an envelope with reduced glycosylation relative to an unmodified virus; and

/or

(iii) a nucleic acid encoding TRIF, or a functional domain thereof.

15. An oncolytic vaccinia virus comprising:

(i) a TK deletion;

(ii) an envelope with reduced glycosylation relative to an unmodified virus; and

/or

(iii) a nucleic acid encoding 15-PGDH, or a functional domain thereof.

16. An oncolytic vaccinia virus comprising:

(i) a TK deletion;

(ii) an envelope with reduced glycosylation relative to an unmodified virus;

(iii) a nucleic acid encoding TRIF, or a functional domain thereof; and

/or

(iv) a nucleic acid encoding 15-PGDH, or a functional domain thereof.

17. An oncolytic vaccinia virus comprising:

(i) a TK deletion;

(ii) an envelope with reduced glycosylation relative to an unmodified virus;

(iii) a nucleic acid encoding TRIF, or a functional domain thereof;

(iv) a nucleic acid encoding 15-PGDH, or a functional domain thereof; and

/or

(v) a C12L deletion.

18. An oncolytic vaccinia virus comprising:

(i) a TK deletion;

(ii) an envelope with reduced glycosylation relative to an unmodified virus;

(iii) a nucleic acid encoding TRIF, or a functional domain thereof;

(iv) a nucleic acid encoding 15-PGDH, or a functional domain thereof;

(v) a C12L deletion; and

/or

(vi) a B5R deletion.