Pretreatment drug for t cell infusion therapy for immune-checkpoint inhibitor-resistant tumor

Abstract

An antigen-loaded nanogel is formed by loading or encapsulating one or more long peptide antigens or one or more protein antigens in a hydrophobized polysaccharide. The long peptide antigen(s) or protein antigen(s) contains (or each contain) one or more CD8+ cytotoxic T cell recognition epitopes and/or one or more CD4+ helper T cell recognition epitopes, which is/are derived from the antigen. The antigen-loaded nanogel may be administered prior to administration of antigen-specific T cells to improve the efficacy of a T cell infusion therapy against an immune checkpoint inhibitor-resistant tumor. The hydrophobized polysaccharide may be pullulan having cholesteryl groups bound thereto. An immune-enhancing agent also may be administered in or with the antigen-loaded nanogel.

1 . A pharmaceutical composition for administration in a T cell infusion therapy against an immune checkpoint inhibitor-resistant tumor prior to administration of T cells specific to an antigen of the immune checkpoint inhibitor-resistant tumor, the pharmaceutical composition comprising:
 an antigen-loaded nanogel comprising one or more long chain peptide antigens or one or more protein antigens loaded in a hydrophobized polysaccharide-based nanogel, the one or more long chain peptide antigens or one or more protein antigens containing one or more CD8+ cytotoxic T cell recognition epitope(s) and/or one or more CD4+ helper T cell recognition epitope(s), which is/are derived from said antigen of the immune checkpoint inhibitor-resistant tumor.   
     
     
         2 . A pharmaceutical composition for T cell infusion therapy against an immune checkpoint inhibitor-resistant tumor, the pharmaceutical composition comprising antigen-specific T cells specific to said antigen to be administered after administration of the antigen-loaded nanogel according to  claim 1 . 
     
     
         3 . The pharmaceutical composition according to  claim 1 , further comprising
 an immune-enhancing agent for administration with the antigen-loaded nanogel, or   an immune-enhancing agent contained in the antigen-loaded nanogel.   
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the antigen-specific T cell is a T cell that expresses a T cell receptor that recognizes the antigen or is a chimeric antigen receptor that recognizes the antigen. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the one or more long chain peptide antigens is (are each) composed of 23 to 120 amino acid residues. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the one or more long chain peptide antigens comprises (each comprise) a sequence selected from the group consisting of 2 to 10 tyrosines, 2 to 10 threonines, 2 to 10 histidines, 2 to 10 glutamines and 2 to 10 asparagines between the T cell recognition epitopes in the long chain peptide antigen. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , wherein the hydrophobized polysaccharide comprises pullulan and cholesteryl groups. 
     
     
         8 . The pharmaceutical composition according to  claim 3 , wherein the immune-enhancing agent is at least one selected from the group consisting of TLR (Toll-like receptor) agonists (CpG oligoDNA or poly-IC RNA), STING agonists or RLR (RIG-I-like receptors) agonists. 
     
     
         9 . The pharmaceutical composition according to  claim 1 , wherein said antigen is a tumor-specific antigen protein or a tumor stroma-specific antigen protein. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the antigen-loaded nanogel is formulated to be administered according to an administration route selected from the group consisting of subcutaneous, intradermal, intramuscular, intratumoral and intravenous. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , wherein the antigen-loaded nanogel is formulated to be administered at least 1 day prior to the administration of the the antigen-specific T cells. 
     
     
         12 . A delivery system for selectively delivering a substance to tumor-associated macrophages when administered intravenously, comprising:
 a nanogel having a particle size of 80 nm or less and composed of a hydrophobized polysaccharide containing pullulan and cholesteryl groups.   
     
     
         13 . A non-human mammal tumor model for identifying effective therapeutic agents for immune checkpoint inhibitor-resistant tumors, wherein the tumor is murine fibrosarcoma CMS5a, and the non-human mammal is a mouse. 
     
     
         14 . The pharmaceutical composition according to  claim 6 , wherein the one or more long chain peptide antigens is (are each) composed of 23 to 80 amino acid residues. 
     
     
         15 . The pharmaceutical composition according to  claim 6 , wherein the one or more long chain peptide antigens is (are each) composed of 23 to 60 amino acid residues. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the one or more CD8+ cytotoxic T cell recognition epitopes and/or the one or more CD4+ helper T cell recognition epitopes is/are derived from the MAGE family, NY-ESO-1/LAGE, SAGE, XAGE, HER2, PRAME, Ras, 5T4, WT1, p53, MUC-1, hTERT, RHAMM, Survivin, EGFRvIII, HPV E6, MART-1, gp100, CEA, IDO, Brachyury, Mesothelin, PSA and PSMA, FAP, the VEGFR family or TEM1. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , further comprising an immune-enhancing agent contained in the antigen-loaded nanogel, wherein the immune-enhancing agent is at least one selected from the group consisting of TLR (Toll-like receptor) agonists (CpG oligoDNA or poly-IC RNA), STING agonists or RLR (RIG-I-like receptors) agonists. 
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the hydrophobized polysaccharide contains pullulan and cholesteryl groups. 
     
     
         19 . A method for treating an immune checkpoint inhibitor-resistant tumor in a patient in need thereof, comprising:
 administering to the patient a therapeutically effective amount of the antigen-loaded nanogel according to  claim 18 ; and   at least one day thereafter, administering to the patient a therapeutically effective amount of antigen-specific T cells that bind to an antigen of the immune checkpoint inhibitor-resistant tumor.   
     
     
         20 . A method for treating an immune checkpoint inhibitor-resistant tumor in a patient in need thereof, comprising:
 administering to the patient a therapeutically effective amount of the antigen-loaded nanogel according to  claim 1 ; and   at least one day thereafter, administering to the patient a therapeutically effective amount of antigen-specific T cells that bind to an antigen of the immune checkpoint inhibitor-resistant tumor.