Engineered virus

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oncolytic virus encoding a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, wherein the virus is a herpes virus.

2. The method of claim 1 , wherein the cancer is a solid tumor.

3. The method of claim 1 , which comprises administering, concurrently or separately to the virus, a therapeutically effective amount of a further anti-cancer agent to a patient in need thereof.

4. The method according to claim 3 , wherein the further anti-cancer agent is selected from an agent targeting an immune co-inhibitory pathway or immune co-stimulatory pathway, radiation and/or chemotherapy, an agent that targets a specific genetic mutation which occurs in tumors, an agent intended to induce an immune response to one or more tumor antigen(s) or neoantigen(s), a cellular product comprising thymus (T) cells or natural killer (NK) cells, an agent intended to stimulate the stimulator of interferon genes (STING), cyclic GMP-AMP synthase (cGAS), toll-like receptor (TLR) or other innate immune response and/or inflammatory pathway, an agent intended to increase or potentiate an immune response, and combinations thereof.

5. The method of claim 4 , wherein the further anti-cancer agent is a CTLA-4 inhibitor, a programmed cell death protein 1 (PD-1) inhibitor, a programmed cell death ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a V-domain immunoglobulin suppressor of T cell activation (VISTA) inhibitor, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, a signaling lymphocytic activation molecule F7 (SLAMF7) inhibitor, a carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) inhibitor or a cluster of differentiation 47 (CD47) inhibitor.

6. The method of claim 4 , wherein the further anti-cancer agent is a glucocorticoid-induced tumor necrosis factor receptor-related (GITR) agonist, a 4-1-BB agonist, an OX40 agonist, a cluster of differentiation 40 (CD40) agonist or an inducible T cell costimulator (ICOS) agonist.

7. A method according to claim 1 , which further comprises administering an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and a further antagonist of an immune co-inhibitory pathway, or an agonist of an immune co-stimulatory pathway.

8. The method of claim 1 , wherein the virus further encodes an immune stimulatory molecule.

9. The method of claim 1 , wherein the virus comprises genes encoding a CTLA-4 inhibitor and one or more of CD40L, ICOSL, 4-1-BBL, GITRL and OX40L.

10. The method of claim 1 , wherein the CTLA-4 inhibitor is a CTLA-4 antibody or fragment thereof.

11. The method of claim 1 , further comprising a GM-CSF-encoding gene.

12. The method of claim 1 , further comprising a fusogenic protein-encoding gene.

13. The method of claim 12 , wherein the fusogenic protein is selected from the group consisting of vesicular stomatitis virus (VSV) G-protein, syncitin-1, syncitin-2, simian virus 5 (SV5) F-protein, measles virus (MV) H-protein, MV F-protein, respiratory syncytial virus (RSV) F-protein and a glycoprotein from gibbon ape leukemia virus (GALV), such as a glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmembrane peptide mutated or removed (GALV-R-), murine leukemia virus (MLV), Mason-Pfizer monkey virus (MPMV) or equine infectious anaemia virus (EIAV) from which the R peptide has been deleted.

14. The method of claim 1 , which is a herpes simplex virus (HSV).

15. The method of claim 14 , which is a HSV1.

16. The method of claim 14 , wherein the HSV:

(a) does not express functional ICP34.5;

(b) does not express functional ICP47; and/or

(c) expresses the US11 gene as an immediate early gene.

17. The method of claim 1 , which is a modified clinical isolate, wherein the clinical isolate is a HSV1:

strain RH018A having the provisional accession number ECCACC 16121904;

strain RH004A having the provisional accession number ECCACC 16121902;

strain RH031A having the provisional accession number ECCACC 16121907;

strain RH040B having the provisional accession number ECCACC 16121908;

strain RH015A having the provisional accession number ECCACC 16121903;

strain RH021A having the provisional accession number ECCACC 16121905;

strain RH023A having the provisional accession number ECCACC 16121906; or

strain RH047A having the provisional accession number ECCACC 16121909.

18. The method of claim 1 , wherein the sequence of the gene encoding the immune co-stimulatory activating molecules are codon optimized so as to increase expression levels of the respective protein(s) in target cells.

19. The method of claim 1 , wherein:

(a) the virus expresses three heterologous genes, wherein each of the three heterologous genes is driven by a different promoter selected from the CMV promoter, the RSV promoter, the EF1a promoter, the SV40 promoter and a retroviral LTR promoter and/or terminated by a different poly adenylation sequence selected from the BGH, SV40, HGH and RBG polyadenylation sequences; or

(b) the virus expresses four heterologous genes, wherein each of the four heterologous genes is driven by a different promoter selected from the CMV promoter, the RSV promoter, the EF1a promoter, the SV40 promoter and a retroviral LTR promoter, and/or terminated by a different poly adenylation sequence selected from the BGH, SV40, HGH and RBG poly adenylation sequences.

20. The method of claim 2 , wherein the solid tumor is an adenocarcinoma.

21. The method of claim 2 , wherein the solid tumor is a carcinoma.

22. The method of claim 2 , wherein the solid tumor is a melanoma.

23. The method of claim 2 , wherein the solid tumor is a sarcoma.

24. The method of claim 1 , comprising administering multiple doses of 10 4 to 10 10 pfu of the oncolytic virus to the subject.

25. The method of claim 1 , wherein the oncolytic virus is administered in an amount effective to induce a systemic anti-tumor immune response.

26. The method of claim 24 , wherein the multiple doses of the oncolytic virus are administered to the subject between 3 days to 3 weeks apart.

27. The method of claim 1 , comprising administering the oncolytic virus directly into the solid tumor.

28. The method of claim 1 , comprising administering the oncolytic virus into a body cavity of the subject.

29. The method of claim 1 , comprising intravenously administering the oncolytic virus to the subject.

30. The method of claim 5 , wherein the further anti-cancer agent is an anti-PD1 antibody.

31. The method of claim 30 , comprising administering the oncolytic virus to the subject prior to administering the anti-PD1 antibody to the subject.

32. The method of claim 31 , comprising administering the oncolytic virus to the subject once prior to administering the anti-PD1 antibody to the subject.

33. The method of claim 31 , comprising administering the oncolytic virus multiple times to the subject prior to administering the anti-PD1 antibody to the subject.

34. The method of claim 30 , comprising administering the oncolytic virus and anti-PD1 antibody to the subject concurrently.

35. The method according to claim 4 , wherein the agent intended to increase or potentiate an immune response is a cytokine, a second virus, a second oncolytic virus, or an antibody.

36. The method of claim 12 , further comprising a gene encoding an immune stimulatory molecule.

37. The method of claim 12 , further comprising a gene encoding an immune co-stimulatory pathway activating molecule.

38. The method of claim 36 , further comprising a gene encoding an immune co-stimulatory pathway activating molecule.

39. The method of claim 1 , further comprising a gene encoding an immune co-stimulatory pathway activating molecule.

40. The method of claim 39 , further comprising a gene encoding an immune stimulatory molecule.