Modified oncolytic virus

1. An oncolytic herpes simplex virus (HSV) comprising: (i) a fusogenic protein-encoding gene, wherein the fusogenic protein is a glycoprotein from gibbon ape leukemia virus (GALV) from which the R peptide has been mutated or removed (GALV-R-); and (ii) one or more immune stimulatory molecules or one or more immune stimulatory molecule-encoding genes, wherein the immune stimulatory molecule is an immune checkpoint antagonist.

2. The virus of claim 1 , wherein the immune stimulatory molecule is GM-CSF, IL-2, IL-12, IL-15, IL-18, IL-21, IL-24, a type I interferon, interferon gamma, a type III interferon, TNF alpha, an antagonist of TGF beta, an immune checkpoint antagonist or an agonist of an immune potentiating pathway.

3. The virus of claim 2 , wherein the immune stimulatory molecule is GM-CSF.

4. The virus of claim 1 , wherein the immune checkpoint antagonist is a CTLA-4 inhibitor.

5. The virus of claim 1 , which encodes more than one immune stimulatory molecule.

6. The virus of claim 5 , wherein the immune stimulatory molecules comprise GM-CSF and a CTLA-4 inhibitor.

7. The virus of claim 5 , wherein the immune stimulatory molecules comprise a CTLA-4 inhibitor and one or more of an agonist of CD40, an agonist of 4-1-BB, an agonist of GITR, an agonist of OX40, an agonist of ICOS and an agonist of flt3.

8. The virus of claim 4 , wherein the CTLA-4 inhibitor is an anti-CTLA4 antibody or a fragment thereof.

9. The virus of claim 1 , which is a HSV1.

10. The virus of claim 1 , which is a modified clinical isolate.

11. The virus of claim 10 , wherein the clinical isolate is an HSV1 strain selected from:

strain RH018A having the accession number ECACC 16121904;

strain RH004A having the accession number ECACC 16121902;

strain RH031A having the accession number ECACC 16121907;

strain RH040B having the accession number ECACC 16121908;

strain RH015A having the accession number ECACC 16121903;

strain RH021A having the accession number ECACC 16121905;

strain RH023A having the accession number ECACC 16121906; or

strain RH047A having the accession number ECACC 16121909.

12. The virus of claim 11 , wherein the HSV1 strain is strain RH018A having the accession number ECACC 16121904.

13. The virus of claim 10 , wherein the virus:

(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.

14. The virus of claim 1 , which:

(a) 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 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; or

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

15. A pharmaceutical composition comprising the virus of claim 1 and a pharmaceutically acceptable carrier or diluent.

16. A product of manufacture comprising the virus of claim 1 in a sterile vial, ampoule or syringe.

17. A method of treating cancer, which comprises administering a therapeutically effective amount of the virus of claim 1 to a patient in need thereof.

18. A method according to claim 17 , which further comprises administering a therapeutically effective amount of a further anti-cancer agent to a patient in need thereof.

19. A method according to claim 18 , wherein the further anti-cancer agent is selected from the group consisting of an agent targeting an immune co-inhibitory 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 of T cells or NK cells, an agent intended to stimulate the STING, cGAS, TLR or other innate immune response and/or inflammatory pathway, a second oncolytic virus, and combinations thereof.

20. A method according to claim 19 , wherein the agent targeting an immune co-inhibitory pathway is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a VISTA inhibitor, aCSF1R inhibitor, an IDO inhibitor, a KIR inhibitor, a SLAMF7 inhibitor a CEACAM1 inhibitor or a CD47 inhibitor and/or the agent targeting an immune co-stimulatory pathway is a GITR agonist, a 4-1-BB agonist, an OX40 agonist, a CD40 agonist or an ICOS agonist.

21. A method according to claim 20 , wherein the further anti-cancer agent comprises an antibody.

22. A method according to claim 18 , wherein the virus and the further anti-cancer agent(s) are administered separately or concurrently.

23. A method according to claim 17 , wherein the cancer is a solid tumor.

24. The virus of claim 2 , wherein the immune stimulatory molecule is an agonist of CD40, ICOS, GITR, 4-1-BB, OX40 or flt3.