Engineered virus

1. An oncolytic virus comprising: (i) a heterologous GM-CSF-encoding gene; and (ii) a heterologous CTLA-4 inhibitor encoding gene, wherein both heterologous genes are inserted into the genome of the virus.

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

3. The virus of claim 1 , further comprising a fusogenic protein-encoding gene.

4. The virus of claim 3 where 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 anaemia virus (EIAV) from which the R peptide has been deleted.

5. The virus of claim 3 , wherein the fusogenic protein is the glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmembrane peptide mutated or removed (GALV-R-).

6. The virus of claim 1 , which encodes more than one immune co-stimulatory pathway activating molecule.

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

8. 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.

9. The virus of claim 7 , wherein the clinical isolate is

strain RH018A having the accession number ECCAC 16121904;

strain RH004A having the accession number ECCAC 16121902;

strain RH031A 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.

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

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

12. The virus of claim 11 which is a HSV1.

13. The virus of claim 11 , wherein the GM-CSF-encoding gene and the CTLA-4 inhibitor encoding gene are inserted into the ICP34.5 encoding locus, either by insertion, or partial or complete deletion, in a back to back orientation in relation to each other, each under separate regulatory control.

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 1 , wherein the sequence of a gene encoding GM-CSF and/or the sequence of the gene encoding a CTLA-4 inhibitor is codon optimized so as to increase expression levels in target cells.

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

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

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

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

20. The method of claim 19 , 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 derived from 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.

21. The method of claim 19 , wherein the virus and the further anti-cancer agent(s) are administered separately.

22. The method of claim 19 , wherein the virus and the further anti-cancer agent(s) are administered concurrently.

23. The method of claim 19 , wherein the cancer is a solid tumor.

24. The method of claim 20 , wherein the further anti-cancer agent comprises an antibody.

25. The method of claim 20 , wherein the further anti-cancer agent is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a VISTA inhibitor, a CSF1R inhibitor, an IDO inhibitor, a KIR inhibitor, a SLAMF7 inhibitor, a CEACAM1 inhibitor or a CD47 inhibitor.

26. The method of claim 20 , wherein the further anti-cancer agent is a GITR agonist, a 4-1-BB agonist, an OX40 agonist, a CD40 agonist or an ICOS agonist.