Armed oncolytic viruses

1. A composition, comprising:

an oncolytic virus comprising a heterologous nucleic acid inserted into the oncolytic virus genome, said nucleic acid comprising a sequence encoding a chimeric human/mouse CD40 ligand operatively linked to a transcriptional control element, wherein the oncolytic virus further comprises one heterologous gene encoding a therapeutic protein, wherein the heterologous gene is selected from the group consisting of genes encoding antibodies, genes encoding pro-drug converting enzymes, and genes encoding checkpoint inhibitors, wherein the chimeric human/mouse CD40 ligand and the therapeutic protein encoded by the one heterologous gene are the only heterologous amino acid sequences expressed by the oncolytic virus.

2. The composition of claim 1 , wherein the oncolytic virus is replication competent.

3. The composition of claim 2 , wherein the replication competent oncolytic virus is selected from herpes simplex virus (HSV), adenovirus, vaccinia virus, poxvirus, coxsackievirus, poliovirus, measles virus, parvovirus, reovirus, Seneca valley virus, Newcastle disease virus, retrovirus, vesicular stomatitis virus, reovirus, paramyxovirus, Sindbis virus, myxoma virus, Maraba virus, influenza virus, measles virus, mumps virus, arenavirus, and Semliki Forest virus.

4. The composition of claim 3 , wherein the replication competent oncolytic virus is a herpes simplex virus.

5. The composition of claim 4 , wherein the replication competent oncolytic herpes simplex virus is selected from the group consisting of herpes simplex virus 1 and herpes simplex virus 2.

6. The composition of claim 4 , wherein the replication competent oncolytic herpes simplex virus lacks a functional ICP34.5 encoding gene.

7. The composition of claim 6 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the ICP34.5 encoding gene region.

8. The composition of claim 4 , wherein the replication competent oncolytic herpes simplex virus lacks a functional ICP47 encoding gene.

9. The composition of claim 1 , wherein the at least one chimeric human/mouse CD40 ligand is selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).

10. The composition of claim 9 , wherein the at least one chimeric human/mouse CD40 ligand is MEM40 (SEQ ID NO:6).

11. The composition of claim 1 , wherein the at least one chimeric human/mouse CD40 ligand has at least 90% identity with a ligand selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).

12. The composition of claim 1 , wherein the transcriptional control element operatively linked to the sequence encoding the CD40 agonist is a transcriptional promoter.

13. The composition of claim 12 , wherein the transcriptional promoter is a cytomegalovirus (CMV) promoter.

14. The composition of claim 4 , wherein the replication competent oncolytic herpes simplex virus is a non-laboratory virus strain.

15. The composition of claim 14 , wherein the replication competent oncolytic herpes simplex virus is derived from an HSV JS1 strain.

16. The composition of claim 1 , further comprising a pharmaceutically-acceptable carrier.

17. A method, comprising:

administering to a patient suffering from a tumor, an oncolytic virus comprising a heterologous nucleic acid inserted into the oncolytic virus genome, said nucleic acid comprising a sequence encoding a chimeric human/mouse CD40 ligand operatively linked to a transcriptional control element, wherein the oncolytic virus further comprises one heterologous gene encoding a therapeutic protein, wherein the heterologous gene is selected from the group consisting of genes encoding antibodies, genes encoding pro-drug converting enzymes, and genes encoding checkpoint inhibitors, wherein the chimeric human/mouse CD40 ligand and the therapeutic protein encoded by the one heterologous gene are the only heterologous amino acid sequences expressed by the oncolytic virus.

18. The method of claim 17 , wherein the oncolytic virus is replication competent.

19. The method of claim 18 , wherein the replication competent oncolytic virus is selected from herpes simplex virus (HSV), adenovirus, vaccinia virus, poxvirus, coxsackievirus, poliovirus, measles virus, parvovirus, reovirus, Seneca valley virus, Newcastle disease virus, retrovirus, vesicular stomatitis virus, reovirus, paramyxovirus, Sindbis virus, myxoma virus, Maraba virus, influenza virus, measles virus, mumps virus, arenavirus, and Semliki Forest virus.

20. The method of claim 19 , wherein the replication competent oncolytic virus is a herpes simplex virus.

21. The method of claim 20 , wherein the replication competent oncolytic herpes simplex virus is selected from the group consisting of herpes simplex virus 1 and herpes simplex virus 2.

22. The method of claim 20 , wherein the replication competent oncolytic herpes simplex virus lacks a functional ICP34.5 encoding gene.

23. The method of claim 22 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the ICP34.5 encoding gene region.

24. The method of claim 20 , wherein the replication competent oncolytic herpes simplex virus lacks a functional ICP47 encoding gene.

25. The method of claim 17 , wherein the at least one chimeric human/mouse CD40 ligand is selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEMA40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).

26. The method of claim 25 , wherein the at least one chimeric human/mouse CD40 ligand is MEM40 (SEQ ID NO:6).

27. The method of claim 17 , wherein the at least one chimeric human/mouse CD40 ligand has at least 90% identity to a ligand selected from the group consisting of ISF30 (SEQ ID NO: 1), ISF31 (SEQ ID NO: 2), ISF32 (SEQ ID NO: 3), ISF33 (SEQ ID NO: 4), ISF34 (SEQ ID NO: 5), ISF35 (MEM40) (SEQ ID NO: 6), ISF36 (SEQ ID NO: 7), ISF37 (SEQ ID NO: 8), ISF38 (SEQ ID NO: 9), ISF39 (SEQ ID NO: 10), ISF40 (SEQ ID NO: 11), and ISF41 (SEQ ID NO: 12).

28. The method of claim 17 , wherein the transcriptional control element operatively linked to the sequence encoding the CD40 ligand is a transcriptional promoter.

29. The method of claim 28 , wherein the transcriptional promoter is a cytomegalovirus (CMV) promoter.

30. The method of claim 20 , wherein the replication competent oncolytic herpes simplex virus is a non-laboratory virus strain.

31. The method of claim 30 , wherein the replication competent oncolytic herpes simplex virus is derived from an HSV JS1 strain.

32. The method of claim 17 , wherein the patient has a cancer selected from primary or metastatic cancer.

33. The method of claim 17 , wherein the oncolytic virus is administered intratumorally, intravenously, intraperitoneally, intratracheally, intramuscularly, intracranially, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, or by direct injection or perfusion.

34. The method of claim 17 , wherein the oncolytic virus is administered once or multiple times.

35. The method of claim 17 , further comprising:

administering at least one additional therapeutic agent.

36. The method of claim 35 , wherein the at least one additional therapeutic agent is chemotherapy, immunotherapy, surgery, radiotherapy, viral therapy, or biotherapy.

37. The method of claim 35 , wherein the at least one additional therapeutic agent is a nonreplicating adenovirus encoding MEM40.

38. The method of claim 35 , wherein the at least one additional therapeutic agent is administered to the patient before administration of the oncolytic virus.

39. The method of claim 35 , wherein the at least one additional therapeutic agent is administered to the patient at the same time as administration of the oncolytic virus.

40. The method of claim 35 , wherein the at least one additional therapeutic agent is administered to the patient after administration of the oncolytic virus.

41. The method of claim 17 , wherein the patient is a human.

42. The composition of claim 1 , wherein the heterologous gene is a gene encoding a checkpoint inhibitor.

43. The composition of claim 42 , wherein the checkpoint inhibitor is selected from the group consisting of anti-PD-1, anti-CDTA4, and anti-PD-L1.