Abrogating proinflammatory cytokine production during oncolytic reovirus therapy

Abstract

Provided herein are methods for treating a proliferative disorder in a subject comprising administering to the subject one or more reoviruses and one or more agents that modulate expression or activity of pro-inflammatory cytokines. For example, the agents may inhibit expression or activity of pro-inflammatory cytokines.

What is claimed is: 
     
         1 . A method for treating a proliferative disorder in a subject, comprising the steps of:
 (a) administering to the subject a reovirus comprising one or more modifications; and   (b) administering to the subject one or more agents that inhibit expression or activity of a pro-inflammatory cytokine but does not inhibit the production of neutralizing anti-reovirus antibodies (NARA).   
     
     
         2 . The method of  claim 1 , wherein the pro-inflammatory cytokine is selected from the group consisting of IL-1I, IL-3, IL-6, IL-12, p70, IL-17, MIP-1I and RANTES. 
     
     
         3 . The method of  claim 1 , wherein the one or more agents block innate and adaptive T-cell responses. 
     
     
         4 . The method of  claim 1 , wherein the one or more agents have no effect on B-cell activity. 
     
     
         5 . The method of  claim 1 , further comprising determining whether the proliferative disorder is a ras-mediated proliferative disorder. 
     
     
         6 . The method of  claim 1 , further comprising selecting a subject with a ras-mediated proliferative disorder. 
     
     
         7 . The method of  claim 1 , wherein the proliferative disorder is caused by a mutation in or dysregulation of PKR. 
     
     
         8 . The method of  claim 1 , wherein the one or more modifications comprises a Leu at residue 979 of the lambda-3 polypeptide. 
     
     
         9 . The method of  claim 1 , wherein the one or more modifications comprises a Lys at residue 198 of the sigma-3 polypeptide. 
     
     
         10 . The method of  claim 1 , wherein the one or more modifications comprises an Asp at residue 73 of the mu-1 polypeptide. 
     
     
         11 . The method of  claim 1 , wherein the one or more modifications comprises a Ser at residue 528 of the mu-2 polypeptide. 
     
     
         12 . The method of  claim 1 , wherein the reovirus comprises a polypeptide selected from the group consisting of SEQ ID NO:18, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16. 
     
     
         13 . The method of  claim 1 , wherein the reovirus comprises SEQ ID NO:18, SEQ ID NO:14, SEQ ID NO:15 and SEQ ID NO:16. 
     
     
         14 . The method of  claim 13 , wherein the reovirus further comprises SEQ ID NO:12. 
     
     
         15 . The method of  claim 1 , wherein the reovirus comprises SEQ ID NOs: 11, 12, and 16-21. 
     
     
         16 . The method of  claim 15 , wherein the reovirus further comprises SEQ ID NO:13 or SEQ ID NO:14. 
     
     
         17 . The method of  claim 15 , wherein the reovirus further comprises SEQ ID NO:13 and SEQ ID NO:14. 
     
     
         18 . The method of  claim 1 , wherein approximately 10 3  to 10 12  plaque forming units (PFU) of the reovirus is administered to the subject. 
     
     
         19 . The method of  claim 1 , wherein approximately 5 to 1000 mg/m 2  of the one or more agents that inhibits proinflammatory cytokines is administered to the subject. 
     
     
         20 . The method of  claim 1 , wherein approximately 0.001-10,000 mg/kg body weight of the one or more agents that inhibits proinflammatory cytokines is administered to the subject. 
     
     
         21 . The method of  claim 1 , wherein the one or more agents are platinum compounds. 
     
     
         22 . The method of  claim 21 , wherein the platinum compounds are selected from the group consisting of cisplatin, carboplatin, oxaliplatin, or a combination thereof. 
     
     
         23 . The method of  claim 22 , wherein approximately 175-200 mg/m 2  of the cisplatin is administered to the subject. 
     
     
         24 . The method of  claim 22 , wherein approximately 200-600 mg/m 2  of the carboplatin is administered to the subject. 
     
     
         25 . The method of  claim 22 , wherein 5 or 6 mg/mL minute (AUC) of the carboplatin is administered to the subject. 
     
     
         26 . The method of  claim 1 , wherein the one or more agents that inhibit pro-inflammatory cytokines are administered at the same time, before or after the reovirus. 
     
     
         27 . The method of  claim 26 , wherein the one or more agents that inhibits pro-inflammatory cytokines are administered at the same time as the reovirus. 
     
     
         28 . The method of  claim 26 , wherein the one or more agents that inhibit pro-inflammatory cytokines is administered before the reovirus. 
     
     
         29 . The method of  claim 28 , wherein the one or more agents are administered from 1 to 12 hours before the reovirus. 
     
     
         30 . The method of  claim 28 , wherein the one or more agent are administered from 1 to 60 minutes before the reovirus. 
     
     
         31 . The method of  claim 1 , wherein the reovirus is administered in multiple doses. 
     
     
         32 . The method of  claim 31 , wherein the one or more agents that inhibit pro-inflammatory cytokines are administered once. 
     
     
         33 . The method of  claim 31 , wherein the one or more agents that inhibits pro-inflammatory cytokines are administered in multiple doses.