Sequence arrangements and sequences for neoepitope presentation

Abstract

Systems and methods are presented that allow for selection of tumor neoepitopes that are then used to generate a recombinant polytope that is optimized for proper trafficking and processing. In preferred methods, the polytope is encoded in a viral expression system that is used as a therapeutic agent.

1 - 123 . (canceled) 
     
     
         124 . A composition comprising:
 (a) an immunostimulatory cytokine;   (b) a means for macrophage suppression; and   (c) an adenovirus, wherein the adenovirus comprises a nucleic acid encoding a heterologous antigen.   
     
     
         125 . The composition of  claim 124 , wherein the means for macrophage suppression is RP 182. 
     
     
         126 . The composition of  claim 125 , wherein the immunostimulatory cytokine is ALT-803. 
     
     
         127 . The composition of  claim 126 , wherein the adenovirus comprises an E1 gene region deletion. 
     
     
         128 . The composition of  claim 127 , wherein the adenovirus comprises an E2b gene region deletion. 
     
     
         129 . The composition of  claim 128 , wherein the heterologous antigen is a neoepitope. 
     
     
         130 . The composition of  claim 128 , wherein the adenovirus further comprises a sequence that encodes a co-stimulatory molecule selected from the group consisting of CD80, CD86, CD30, CD40, CD30L, CD40L, ICOS-L, B7-H3, B7-H4, CD70, OX40L, 4-1BBL, GITR-L, TIM-3, TIM-4, CD48, CD58, TL1A, ICAM-1, and LFA3. 
     
     
         131 . The composition of  claim 128 , wherein the adenovirus further comprises a sequence that encodes a protein that interferes with checkpoint inhibition, and wherein the protein that interferes is an antagonist of CTLA-4, PD-1, TIM1 receptor, 2B4, or CD160. 
     
     
         132 . A composition comprising:
 (d) a first adenovirus, wherein the first adenovirus comprises a nucleic acid encoding an immunostimulatory cytokine;   (e) a means for macrophage suppression; and   (f) a second adenovirus, wherein the second adenovirus comprises a nucleic acid encoding a heterologous antigen.   
     
     
         133 . The composition of  claim 132 , wherein the means for macrophage suppression is RP 182. 
     
     
         134 . The composition of  claim 133 , wherein the immunostimulatory cytokine is ALT-803. 
     
     
         135 . The composition of  claim 134 , wherein the first and second adenoviruses each comprise an E1 gene region deletion. 
     
     
         136 . The composition of  claim 135 , wherein the first and second adenoviruses each comprise an E2b gene region deletion. 
     
     
         137 . The composition of  claim 136 , wherein the heterologous antigen is a neoepitope. 
     
     
         138 . The composition of  claim 136 , wherein the second adenovirus further comprises a sequence that encodes a co-stimulatory molecule selected from the group consisting of CD80, CD86, CD30, CD40, CD30L, CD40L, ICOS-L, B7-H3, B7-H4, CD70, OX40L, 4-1BBL, GITR-L, TIM-3, TIM-4, CD48, CD58, TL1A, ICAM-1, and LFA3. 
     
     
         139 . The composition of  claim 136 , wherein the second adenovirus further comprises a sequence that encodes a protein that interferes with checkpoint inhibition, and wherein the protein that interferes is an antagonist of CTLA-4, PD-1, TIM1 receptor, 2B4, or CD160. 
     
     
         140 . A composition comprising:
 (g) a first adenovirus, wherein the first adenovirus comprises a nucleic acid encoding an immunostimulatory cytokine;   (h) a second adenovirus, wherein the second adenovirus comprises a nucleic acid encoding a means for macrophage suppression; and   (i) a third adenovirus, wherein the second adenovirus comprises a nucleic acid encoding a heterologous antigen.   
     
     
         141 . The composition of  claim 140 , wherein the means for macrophage suppression is RP 182. 
     
     
         142 . The composition of  claim 141 , wherein the immunostimulatory cytokine is ALT-803. 
     
     
         143 . The composition of  claim 142 , wherein the first, second, and third adenoviruses each comprise an E1 gene region deletion and an E2b gene region deletion.