Biomarkers and combination therapies using oncolytic virus and immunomodulation

Abstract

The invention disclosed herein describes biomarkers useful for prognosis, selection and monitoring of oncolytic virus therapy for patients with various types of cancer. In particular, the present invention provides identification of proteins whose expression patterns are strongly predictive of the outcome of oncolytic virus therapy in a patient with cancer. The present invention provides a method for identifying and selecting cancer patients who are likely to be non-responsive to onocolytic virus therapy. These patients can be co-administered an agent that stimulates a cell-mediated immune response in the patient with the oncolytic virus or can be administered a therapy other than oncolytic virus therapy.

1 - 47 . (canceled) 
     
     
         48 . A method for treating cancer in a patient having or suspected of having a primary or metastatic brain tumor comprising administering to said patient (a) an oncolytic virus selected from the group consisting of Delta-24 and Delta-24 RGD; and (b) a Th1 stimulating agent. 
     
     
         49 . The method of  claim 48 , wherein said Th1 stimulating agent is an agent which upregulates or activates the cellular immune system. 
     
     
         50 . The method of  claim 49 , wherein said agent which upregulates or activates the cellular immune system is a cytokine selected from the group consisting of recombinant IL-12p70 and recombinant IFN-gamma. 
     
     
         51 . The method of  claim 49 , wherein said agent which upregulates or activates the cellular immune system is an agent selected from the group consisting of Revlimid and lenadlidomide. 
     
     
         52 . The method of  claim 48 , wherein said Th1 stimulating agent is an agent which suppresses regulatory T cells. 
     
     
         53 . The method of  claim 52 , wherein the agent which suppresses regulatory T cells is selected from the group consisting of temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0]nona-2,7,9-triene-9-carboxamide), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide), lomustine (CCNU; N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea), bis-chloroethylnitrosourea (BCNU), melphalan hydrochloride (4[bis(chloroethyl)amino]phenylalanine), and busulfan (butane-1,4-diyldimethanesulfonate). 
     
     
         54 . The method of claim  47 , wherein said Th1 stimulating agent is an agent which is an antagonist of a suppressor of cellular immunity. 
     
     
         55 . The method of  claim 54 , wherein said agent which is an antagonist of a suppressor of cellular immunity is an antagonist of CTLA-4. 
     
     
         56 . The method of  claim 55 , wherein said agent is selected from the group consisting of Ipilimumab, MDX-010, MDX-101, Tremelimumab, and CP-675,206. 
     
     
         57 . The method of claim  47 , wherein said agent which is an antagonist of a suppressor of cellular immunity is a PD-1/PD-L1 receptor antagonist. 
     
     
         58 . The method of  claim 57 , wherein said agent is selected from the group consisting of MDX-1106, MK-3475, AMP-224, Pidilizumab, and MDX-1105. 
     
     
         59 . The method of claim  47 , wherein the virus is administered intratumorally. 
     
     
         60 . The method of  claim 59 , wherein the virus is administered intratumorally by injection into multiple tumor sites. 
     
     
         61 . The method of claim  47 , wherein the virus is administered intravascularly, such as intravenously or intraarterially. 
     
     
         62 . The method of claim  47 , wherein said brain tumor is a glioma. 
     
     
         63 . The method of  claim 62 , wherein the glioma is low-grade glioma. 
     
     
         64 . The method of  claim 62 , wherein the glioma is high-grade glioma. 
     
     
         65 . The method of claim  47 , wherein the oncolytic virus is administered to the patient prior to the Th1 stimulating agent. 
     
     
         66 . The method of claim  47 , wherein the oncolytic virus is administered to the patient after the Th1 stimulating agent. 
     
     
         67 . The method of claim  47 , where the brain tumor is primary brain tumor. 
     
     
         68 . The method of claim  47 , where the brain tumor is metastatic brain tumor.