Method for Treating Melanoma Using a Herpes Simplex Virus and an Immune Checkpoint Inhibitor

Abstract

The invention relates to methods of treating melanoma using a herpes simplex virus in combination with an immune checkpoint inhibitor.

1 . A method for the treatment of melanoma comprising administering to a patient with stages IIIb to IV melanoma an effective amount of an immune checkpoint inhibitor and a herpes simplex virus, wherein the herpes simplex virus lacks functional ICP34.5 genes, lacks a functional ICP47 gene and comprises a gene encoding human GM-CSF. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . A kit comprising a herpes simplex virus lacking functional ICP34.5 genes, lacking a functional ICP47 gene and comprising a gene encoding human GM-CSF and 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. 
     
     
         5 . (canceled) 
     
     
         6 . The method according to  claim 1 , wherein the administration of the herpes simplex virus precedes the administration of the immune checkpoint inhibitor. 
     
     
         7 . The method according to  claim 1 , wherein the checkpoint inhibitor is an anti-CTLA-4 antibody. 
     
     
         8 . The method of  claim 7 , wherein the anti-CTLA-4 antibody is ipilimumab. 
     
     
         9 . The method according to  claim 1 , wherein the herpes simplex virus is talimogene laherparepvec. 
     
     
         10 . The method according to  claim 1 , wherein the checkpoint inhibitor is a PD1 blocker. 
     
     
         11 . The method according to  claim 1 , wherein the checkpoint inhibitor is a PD-L1 blocker. 
     
     
         12 . The method according to  claim 1 , wherein the checkpoint inhibitor is an anti-PD-L1 antibody. 
     
     
         13 . The method according to  claim 1 , wherein the checkpoint inhibitor is an anti-PD1 antibody. 
     
     
         14 . The method according to  claim 10 , wherein the PD1 blocker is selected from the group consisting of nivolumab, lambrolizumab, CT-011, and AMP-224. 
     
     
         15 . The method according to  claim 11 , wherein the PD-L1 blocker is BMS-936559. 
     
     
         16 - 21 . (canceled) 
     
     
         22 . The kit according to  claim 4 , wherein the directions to treat stages IIIb to IV melanoma comprise instructions to administer to a patient with stages IIIb to IV melanoma 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 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. 
     
     
         23 . A method of manufacturing the kit of  claim 4 .