Immunotherapy of cancer

Abstract

Immunogenic modulators and compositions comprising oligonucleotide agents capable of inhibiting suppression of immune response by reducing expression of one or more gene involved with an immune response suppression mechanism.

1 . An immune modulator comprising an sdRNA, wherein the sdRNA comprises a guide strand and a passenger strand, wherein the guide strand is about 19-25 nucleotides long, and the passenger strand is about 10-19 nucleotides long, wherein the sdRNA includes a double stranded region and a single stranded region, wherein the single stranded region includes 5-9 phosphorothioate modifications, wherein the sdRNA is chemically modified, including at least one 2′-O-methyl modification or 2′-fluoro modification, and wherein the sdRNA is capable of suppressing expression of HAVCR2. 
     
     
         2 . An immunogenic composition comprising an sdRNA, wherein the sdRNA comprises a guide strand and a passenger strand, wherein the guide strand is about 19-25 nucleotides long, and the passenger strand is about 10-19 nucleotides long, wherein the sdRNA includes a double stranded region and a single stranded region, wherein the single stranded region includes 5-9 phosphorothioate modifications, wherein the sdRNA is chemically modified, including at least one 2′-O-methyl modification or 2′-fluoro modification, wherein the sdRNA is capable of suppressing expression of HAVCR2, and wherein the immunogenic composition further comprises immune cells modified by the sdRNA to suppress expression of HAVCR2. 
     
     
         3 . The immunogenic composition of  claim 2 , wherein the immune cells within the composition are further modified to suppress expression of a plurality of immune checkpoint genes. 
     
     
         4 . The immunogenic composition of  claim 2 , wherein said cells are modified to suppress expression of at least one immune checkpoint gene, and at least one gene selected from the group consisting of: an anti-apoptosis gene, a cytokine receptor gene, and a regulator gene. 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The immunogenic composition of  claim 3 , wherein said modified cells further comprise one or more sdRNA capable of suppressing expression of at least one target gene selected from the group consisting of: CTLA4, PD1/PDCD1, TGFBR1, TGFRBR2, IL10RA, TP53, BAX, BAK1, CASP8, ADORA2A, LAG3, CCL17, CCL22, DLL2, FASLG, CD274, IDO1, ILIORA, JAG1, JAG2, MAPK14, SOCS1, STAT3, TNFAIP3, TYRO3, BTLA, KIR, B7-H3 receptor, and B7-H4 receptor. 
     
     
         10 . The immunogenic composition of  claim 9 , wherein said cells are selected from the group consisting of T-cells, NK-cells, antigen-presenting cells, dendritic cells, stem cells, induced pluripotent stem cells, and/or stem central memory T-cells. 
     
     
         11 . The immunogenic composition of  claim 9 , wherein said cells are T-cells comprising one or more transgene expressing high affinity T-cell receptors (TCR) and/or chimeric antibody-T-cell receptors (CAR). 
     
     
         12 . (canceled) 
     
     
         13 . The immunogenic composition of  claim 9 , wherein said cells comprise one or more sdRNA targeting one or more anti-apoptotic genes selected from the group consisting of BAX, BAC, TP53, and Casp8. 
     
     
         14 . (canceled) 
     
     
         15 . The immunogenic composition of  claim 9 , wherein said sdRNA comprises at least one 2′-O-methyl modification and/or at least one 2′-O-Fluoro modification, and at least one phosphorothioate modification. 
     
     
         16 . The immunogenic composition of  claim 9 , wherein said sdRNA comprises at least one hydrophobic modification. 
     
     
         17 . The immunogenic composition of  claim 9 , wherein said sdRNA is modified to comprises at least one cholesterol molecule. 
     
     
         18 . The immunogenic composition of  claim 9 , wherein said sdRNA targets a sequence selected from SEQ ID NOs: 1-360 and 381-1000. 
     
     
         19 . A method of producing the immunogenic composition of  claim 3 , said method comprising transforming at least one cell with one or more sdRNA capable of targeting and suppressing expression of one or more immune target genes, wherein at least one sdRNA interferes with HAVCR2 expression. 
     
     
         20 . The method of  claim 19 , wherein the at least one cell comprises an sdRNA that inhibits expression of one or more genes selected from the group consisting of: CTLA4, PD1/PDCD1, TGFBR1, TGFRBR2, IL10RA, TP53, BAX, BAK1, CASP8, ADOARA2A, LAG3, CCL17, CCL22, DLL2, FASLG, CD274, IDO1, ILIORA, JAG1, JAG2, MAPK14, SOCS1, STAT3, TNFAIP3, TYRO3, BTLA, KIR, B7-H3 receptor, and B7-H4 receptor. 
     
     
         21 . The method of  claim 19 , wherein said cells are selected from the group consisting of T-cells, NK-cells, antigen-presenting cells, dendritic cells, stem cells, induced pluripotent stem cells, and/or stem central memory T-cells. 
     
     
         22 - 24 . (canceled) 
     
     
         25 . A method for treating a subject having proliferative disease or infectious disease, the method comprising administering to the subject the immune modulator of  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein said proliferative disease is cancer. 
     
     
         27 . The method of  claim 25 , wherein said infectious disease is a pathogen infection. 
     
     
         28 . (canceled) 
     
     
         29 . The immune modulator of  claim 1 , wherein at least one sdRNA targets a sequence selected from SEQ ID NOs: 361-380. 
     
     
         30 . The immunogenic composition of  claim 2 , wherein at least one sdRNA targets a sequence selected from SEQ ID NOs: 361-380.