Method for treating melanoma using a herpes simplex virus and an immune checkpoint inhibitor

1. A method for the treatment of melanoma, said method comprising administering to a patient with stages IIIb to IV melanoma:

(i) an effective amount of an anti-PD-1 antibody or anti-CTLA-4 antibody; and

(ii) a herpes simplex virus, wherein said herpes simplex virus:

lacks a functional ICP34.5 encoding gene;

lacks a functional ICP47 encoding gene; and

comprises a gene encoding human GM-CSF.

2. A kit comprising:

(i) a herpes simplex virus, wherein said herpes simplex virus:

lacks a functional ICP34.5 gene;

lacks a functional ICP47 gene; and

comprises a gene encoding human GM-CSF; and

(ii) a package insert or label with directions to treat stages IIIb to IV melanoma by using a combination of the herpes simplex virus and an immune checkpoint inhibitor, wherein said immune checkpoint inhibitor is an anti-PD-1 or anti-CTLA-4 antibody.

3. A method for the treatment of melanoma, said method comprising administering to a patient with stages IIIb to IV melanoma:

(i) a herpes simplex virus, wherein said herpes simplex virus:

lacks a functional ICP34.5 gene;

lacks a functional ICP47 gene; and

comprises a gene encoding human GM-CSF, and

wherein said herpes simplex virus is administered by intratumoral injection at a dose of up to 4.0 ml of 10 6 PFU/mL at day 1 of week 1 followed by a dose of up to 4.0 ml of 10 8 PFU/mL at day 1 of week 4, and every 2 weeks thereafter until complete response; and

(ii) an anti-CTLA-4 antibody,

wherein said anti-CTLA-4 antibody is administered intravenously at a dose of 3 mg/kg every 3 weeks for 4 infusions beginning after the third dose of said herpes simplex virus.

4. The method according to claim 1 , wherein said anti-PD-1 antibody or anti-CTLA-4 antibody is an IgG antibody.

5. The method of claim 1 , wherein the anti-CTLA-4 antibody is ipilimumab.

6. The method according to claim 1 or 4 , wherein the administration of the herpes simplex virus precedes the administration of the anti-PD-1 or anti-CTLA-4 antibody.

7. The method according to claim 1 or 4 , wherein the herpes simplex virus is talimogene laherparepvec.

8. The method according to claim 1 , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, lambrolizumab, CT-011, and AMP-224.

9. The kit according to claim 2 , wherein the directions to treat stages IIIb to IV melanoma comprise instructions to administer to a patient with stages IIIb to IV melanoma:

(i) a herpes simplex virus administered by intratumoral injection into injectable cutaneous, subcutaneous, and nodal tumors at a dose of up to 4.0 ml of 10 6 PFU/mL at day 1 of week 1 followed by a dose of up to 4.0 ml of 10 8 PFU/mL at day 1 of week 4, and every 2 weeks thereafter until complete response; and

(ii) an anti-CTLA-4 antibody administered intravenously at a dose of 3 mg/kg every 3 weeks for 4 infusions beginning after the third dose of the herpes simplex virus.

10. A method of manufacturing the kit of claim 2 .

11. The method according to claim 1 , wherein:

said herpes simplex virus is talimogene laherparepvec; and

said anti-CTLA-4 antibody is ipilimumab.

12. The method according to claim 3 , wherein:

said herpes simplex virus is talimogene laherparepvec; and

said anti-CTLA-4 antibody is ipilimumab.

13. The method according to claim 3 or 12 , wherein said herpes simplex virus is administered by intratumoral injection into injectable cutaneous, subcutaneous, and nodal tumors.

14. The kit according to claim 2 or 9 , wherein said anti-PD-1 antibody or anti-CTLA-4 antibody is an IgG antibody.

15. The method according to claim 1 , wherein said anti-PD-1 antibody is lambrolizumab or nivolumab.

16. The method according to claim 1 , wherein:

said herpes simplex virus is talimogene laherparepvec; and

said anti-PD-1 antibody is lambrolizumab or nivolumab.

17. The kit according to claim 2 , wherein said anti-PD-1 antibody is lambrolizumab or nivolumab.

18. The kit according to claim 2 , wherein:

said herpes simplex virus is talimogene laherparepvec; and

said anti-PD-1 antibody is lambrolizumab or nivolumab.

19. The kit according to claim 2 , wherein:

said herpes simplex virus is talimogene laherparepvec; and

said anti-CTLA-4 antibody is ipilimumab.