ENGINEERED SYNERGISTIC ONCOLYTIC VIRAL SYMBIOSIS

• US 20110206640A1
• Filed: 08/20/2009
• Published: 08/25/2011
• Est. Priority Date: 08/21/2008
• Status: Active Grant

• Current Assignee: Turnstone Limited Partnership
• Original Assignee: Ottawa Hospital Research Institute (Ottawa Hospital)
• Inventors: Le Boeuf, Fabrice, Bell, John C.
• Granted Patent: US 10,603,351 B2
• Time in Patent Office: Days
• US Class Current: 424/93.2
• 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 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 35/766 Rhabdovirus, e.g. vesicular stomatitis virus
• CPC Class Codes: A61K 38/162 from virus
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 2710/24132 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2760/20232 Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent

Abstract

In one aspect, the invention provides methods for preferentially killing target proliferating cells in a host, such as cancer cells, by infecting host tissues with two or more strains of virus. The strains of virus may be selected to provide a synergistic and symbiotic effect, involving a contemporaneous lytic infection in the target proliferating cells. In selected embodiments, the viruses are selected so that expression of a first virulence factor in proliferating cells infected with the first virus increases the lytic effect of the second virus; and, expression of the second virulence factor in proliferating cells infected with the second virus increases the lytic effect of the first virus. The genomes of the first and second viruses may be selected so that they are incompatible for recombination between the viral genomes in cells of the host.

Claims

1. A method of selectively ablating proliferating cells in a host, comprising administering an effective amount of each of a combination of lytic viruses to the host so as to induce a contemporaneous synergistic lytic infection in the proliferating cells by the viruses, wherein the combination comprises:

a first recombinant lytic virus having a genome encoding a first virulence factor; and

,

a second recombinant lytic virus having a genome encoding a second virulence factor;

wherein expression of the first virulence factor in proliferating cells infected with the first virus increases the lytic effect of the second virus; and

, expression of the second virulence factor in proliferating cells infected with the second virus increases the lytic effect of the first virus; and

the genomes of the first and second viruses are incompatible for recombination between the viral genomes in cells of the host.

2. The method of claim 1, wherein the host is a human patient.

3. The method of claim 1, wherein the proliferating cells are cancer cells.

4. The method of claim 1, wherein the first and second viruses are oncolytic viruses.

5. The method of claim 1, wherein the genome of the first virus does not encode the second virulence factor.

6. The method of claim 1, wherein the genome of the second virus does not encode the first virulence factor.

7. The method of claim 1, wherein:

the genome of the first virus is a DNA genome and the genome of the second virus is an RNA genome, and the second virus is not a Retroviridae;

or,

the genome of the first virus is an RNA genome and the genome of the second virus is a DNA genome, and the first virus is not a Retroviridae;

or,

the genome of the first virus is a positive sense RNA genome and the genome of the second virus is a negative sense RNA genome;

or,

the genome of the first virus is a negative sense RNA genome and the genome of the second virus is a positive sense RNA genome;

or,

the genome of the first virus is a double stranded RNA genome and the genome of the second virus is a single stranded RNA genome;

or,

the genome of the first virus is a single stranded RNA genome and the genome of the second virus is a double stranded RNA genome.

8. The method of claim 1, wherein the first virus or the second virus is a vaccinia virus (VV).

9. The method of claim 1, wherein the first virus or the second virus is a vesicular stomatitis virus (VSV).

10. The method of claim 1, wherein the first virus is a VV.

11. The method of claim 1, wherein the second virus is a VSV.

12. The method of claim 8, wherein the VV does not express functional thymidine kinase.

13. The method of claim 8, wherein the VV expresses GM-CSF.

14. The method of claim 8, wherein the VV does not express functional vaccinia growth factor.

15. The method of claim 9, wherein the VSV does not express matrix (M) protein that is non-functional for disrupting anti-viral responses.

16. The method of claim 1, wherein the first and/or second virulence factor is/are a viral virulence factor.

17. The method of claim 1, wherein the first and second virulence factors are:

a soluble interferon binding protein;

a vaccinia growth factor;

a complement control protein;

a vaccinia virus complement control protein;

a viral IL-17;

a Yaba-like disease virus protein Y136;

a B8R protein;

a protease;

a MMP;

a trypsin;

a Yaba Monkey Tumour Virus 2L protein;

a membrane fusion protein;

or, a FAST membrane fusion protein.

18. The method of claim 1, wherein the first virulence factor is a soluble interferon (IFN) binding protein.

19. The method of claim 18, wherein the soluble IFN binding protein is a protein having at least 80% amino acid sequence identity to a VV B18R protein sequence.

20. The method of claim 19, wherein the VV B18R protein sequence has the amino acid sequence of Genbank Accession Number BAA00826.

21. The method of claim 1, wherein the second virulence factor is a membrane fusion protein.

22. The method of claim 21, wherein the membrane fusion protein is a protein having at least 80% amino acid sequence identity to a reovirus Fusion Associated Small Transmembrane (FAST) protein sequence.

23. The method of claim 22, wherein the FAST protein is a p14 protein of a reptilian reovirus.

24. The method of claim 23, wherein the p14 protein has the amino acid sequence of Genbank Accession Number AAP03134.

25. The method of claim 1, wherein the first virus is administered before the second virus.

26. A method of treating a cancer in a human patient comprising administering an effective amount of each of a combination of oncolytic viruses to the patient so as to induce a contemporaneous synergistic oncolytic infection of cancer cells by the viruses, wherein the combination comprises:

a VV expressing a soluble IFN binding protein; and

,

a VSV expressing a membrane fusion protein.

27-31. -31. (canceled)

32. A method of treating a cancer in a human patient comprising administering to the patient an effective amount of a VSV expressing a reovirus Fusion Associated Small Transmembrane (FAST) protein.

33. (canceled)

34. (canceled)

35. A method of treating a cancer in a human patient comprising administering an effective amount of each of a combination of oncolytic viruses to the patient so as to induce a contemporaneous oncolytic infection in cancer cells by the viruses, wherein the combination comprises:

a VV lacking a functional E3L gene and expressing a soluble IFN binding protein; and

,

a VSV.

36. A method of selectively ablating proliferating cells in a host, wherein the host comprises:

a non-target tissue having a non-target anti-viral interferon response; and

,

a target tissue comprising the proliferating cells, the target tissue having a target interferon response;

the method comprising administering to the host an effective amount of at least two recombinant virus strains, a priming virus and a targeted virus, wherein infection of the target tissue by the priming virus augments a targeting virus infection of the proliferating cells by down-regulating the target interferon response, and wherein the non-target anti-viral interferon response remains effective in the non-target tissues to ameliorate infection of the non-target tissue by the targeted virus, whereby lytic infection of the targeting virus is selective for the proliferating cells of the target tissue compared to cells of the non-target tissue.

37-43. -43. (canceled)