Modified oncolytic virus

1. An oncolytic virus comprising: (i) a heterologous fusogenic protein-encoding gene; and (ii) an immune stimulatory molecule or an immune stimulatory molecule-encoding gene.

2. The virus of claim 1 , 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), murine leukemia virus (MLV), Mason-Pfizer monkey virus (MPMV) and equine infectious anemia virus (EIAV) from which the R peptide has been deleted.

3. 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 such as an agonist of CD40, ICOS, GITR, 4-1-BB, OX40 or flt3, optionally_CD40 ligand (CD40L), ICOS ligand, GITR ligand, 4-1-BB ligand, OX40 ligand or flt3 ligand.

4. The virus of claim 1 , wherein:

(a) the fusogenic protein is the glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmembrane peptide mutated or removed (GALV-R−); and/or

(b) the immune stimulatory molecule is (i) GM-CSF or an agonist of CD40, ICOS, GITR, 4-1-BB, OX40 or flt3, optionally CD40L, GITR ligand, 4-1-BB ligand, OX40 ligand, ICOS ligand flt3 ligand; or (ii) a CTLA-4 inhibitor.

5. The virus of claim 1 , which encodes more than one fusogenic protein and/or more than one immune stimulatory molecule.

6. The virus of claim 5 where the immune stimulatory molecules are GM-CSF and one or more of (i) an agonist of CD40, ICOS, GITR, 4-1-BB, OX40 or flt3, optionally CD40L, GITR ligand, 4-1-BB ligand, OX40 ligand and ICOS ligand or flt3; and/or (ii) a CTLA-4 inhibitor.

7. The virus of claim 4 , wherein the CTLA-4 inhibitor is a CTLA-4 antibody or a fragment thereof.

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

9. The virus of claim 1 , which is a modified clinical isolate of a virus, wherein the clinical isolate kills two or more tumor cell lines more rapidly and/or at a lower dose in vitro than one or more reference clinical isolates of the same species of virus.

10. The virus of claim 8 , wherein the clinical isolate is

strain RH018A having the accession number ECCAC 16121904;

strain RH004A having the accession number ECCAC 16121902;

strain RH031 A having the accession number ECCAC 16121907;

strain RH040B having the accession number ECCAC 16121908;

strain RH015A having the accession number ECCAC 16121903;

strain RH021A having the accession number ECCAC 16121905;

strain RH023A having the accession number ECCAC 16121906; or

strain RH047A having the accession number ECCAC 16121909.

11. The virus of claim 1 , which is selected from the group consisting of herpes viruses, pox viruses, adenoviruses, retroviruses, rhabdoviruses, paramyxoviruses and reoviruses.

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

13. The virus of claim 12 which is a HSV1.

14. The virus of claim 12 , 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.

15. The virus of claim 12 , wherein a fusogenic protein-encoding gene and an immune stimulatory molecule-encoding gene are inserted into the ICP34.5 encoding locus, either by insertion, or partial or complete deletion, each under separate regulatory control, optionally in a back to back orientation in relation to each other.

16. The virus of claim 1 , wherein the sequence of a gene encoding the fusogenic protein and/or the sequence of the gene encoding an immune stimulatory molecule is codon optimized so as to increase expression levels in target cells.

17. A virus according to claim 1 , which 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.

18. The virus of claim 17 , which expresses four heterologous genes driven by each of the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR promoter, respectively.

19. The virus of claims g, where the retroviral LTR is from MMLV.

20. A virus according to claim 1 , which expresses three heterologous genes, wherein each of the three heterologous genes is terminated by a different poly adenylation sequence selected from the BGH, SV40, HGH and RBG poly adenylation sequences.

21. The virus of claim 20 , which expresses four heterologous genes terminated by each of the BGH, SV40, HGH and RBG poly adenylation sequences, respectively.

22. A pharmaceutical composition comprising a virus according to claim 1 and a pharmaceutically acceptable carrier or diluent.

23. A product of manufacture comprising a virus according to claim 1 in a sterile vial, ampoule or syringe.

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

25. The method of claim 24 , which further comprises administering a therapeutically effective amount of a further anti-cancer agent to a patient in need thereof.

26. The method of claim 25 , 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 virus optionally an oncolytic virus, and combinations thereof.

27. The method of claim 26 , 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, aCSFIR inhibitor, an IDO inhibitor, a KIR inhibitor, a SLAMF7 inhibitor a CEACAM 1 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.

28. The method of claim 25 , wherein the further anti-cancer agent comprises an antibody.

29. The method of claim 25 , wherein the virus and the further anti-cancer agent(s) are administered separately.

30. The method of claim 25 , wherein the virus and the further anti-cancer agent(s) are administered concurrently.

31. The method of claim 25 , wherein the cancer is a solid tumor.