Use of an oncolytic virus for the treatment of cancer
The present invention provides a method of treating cancer, which comprises administering a therapeutically effective amount of an oncolytic virus, 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 to a patient in need thereof.
1. A method of treating cancer, which comprises administering to a patient in need thereof a combination of agents consisting essentially of: (i) a therapeutically effective amount of an oncolytic virus; (ii) a therapeutically effective amount of an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway; and (iii) a therapeutically effective amount of one of: (a) a further antagonist of an immune co-inhibitory pathway; and (b) an agonist of an immune co-stimulatory pathway.
2. A method according to claim 1 wherein the further antagonist of an immune co-inhibitory pathway is an antagonist of CTLA-4, an antagonist of PD1 or an antagonist of PD-L1.
3. A method according to claim 1 , wherein the further antagonist of an immune co-inhibitory pathway is an inhibitor of the interaction between PD1 and PD-L1.
4. A method according to 1, wherein the antagonist is an antibody or an antibody fragment.
5. A method according to claim 1 , wherein the inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway is 1-methyl trypotophan, epacadostat (INCB024360), Indoximod (1-methyly-D-tryptophan), GDC-0919 or F001287.
6. A method according to claim 1 , wherein the oncolytic virus expresses an immune stimulating molecule and/or a fusogenic protein.
7. A method according to claim 6 , 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, UV 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.
8. A method according to claim 7 , wherein the fusogenic protein is the GALV fusogenic glycoprotein with the R sequence mutated or deleted.
9. A method according to claim 6 , 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, such as a CTLA-4 inhibitor, 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.
10. A method according to claim 9 , wherein the immune stimulatory molecule is GM-CSF.
11. A method according to claim 1 , wherein the virus encodes more than one fusogenic protein and/or more than one immune stimulatory molecule.
12. A method according to claim 11 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 ligand; and (ii) a CTLA-4 inhibitor.
13. A method according to claim 12 , wherein the CTLA-4 inhibitor is a CTLA-4 antibody or a fragment thereof.
14. A method according to claim 1 , wherein the oncolytic virus is a clinical isolate.
15. A method according to claim 14 , 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.
16. A method according to claim 14 , 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.
17. A method according to claim 1 , wherein the oncolytic virus is selected from the group consisting of herpes viruses, pox viruses, adenoviruses, retroviruses, rhabdoviruses, paramyxoviruses and reoviruses.
18. A method use according to claim 17 , wherein the herpes virus is a HSV.
19. A method according to claim 18 , wherein the HSV is a HSV1.
20. A method according to claim 18 , wherein the HSV does not express functional ICP34.5, does not express functional ICP47 and/or expresses the US11 gene as an immediate early gene.
21. A method according to claim 17 , wherein the HSV is rendered functionally inactive for ICP34.5 and/or ICP47.
22. A method according to claim 20 , 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.
23. A method according to claim 6 , 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.
24. A method according to claim 1 , wherein the oncolytic 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 SV40 promoter and a retroviral LTR promoter.
25. A method according to claim 24 , wherein the oncolytic virus expresses four heterologous genes driven by each of the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR promoter, respectively.
26. A method according to claim 24 , wherein the wherein the retroviral LTR promoter is from MMLV.
27. A method according to claim 1 , wherein the oncolytic virus expresses three heterologous genes, wherein each of the three heterologous genes is terminated by a different polyadenylation sequence selected from the BGH, SV40, HGH and RBG polyadenylation sequences.
28. A method according to claim 27 , wherein the oncolytic virus expresses four heterologous genes terminated by each of the BGH, SV40, HGH and RBG poly adenylation sequences, respectively.
29. A method according to claim 1 , wherein the cancer s a solid tumor.