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.

Description

TECHNICAL FIELD[0001]The invention relates to a pretreatment drug that enhances the efficacy of T cell infusion therapy against immune checkpoint inhibitor-resistant tumors.BACKGROUND ART[0002]T cells play important roles in tumor immune response. T cells recognize antigen protein-derived epitope peptides bound to major histocompatibility complex (MHC) presented on the surface of antigen presenting cells (dendritic cells, macrophages, etc.) through T cell receptors (TCR) expressed on the surface of the T cells. The reaction is called antigen stimulation. Simultaneously with antigen stimulation, co-stimulatory signals are generated by binding between membrane protein CD28 on the T cells and membrane protein CD80 or CD86 on the antigen presenting cells. T cells are appropriately activated by TCR signals via antigen stimulation and by co-stimulatory signals.[0003]In opposition thereto, a regulatory mechanism called immune checkpoint is provided for preventing T cell activity from becom...

AI Technical Summary

Benefits of technology

[0036]According to the present invention, useful pharmaceutical compositions can be provided for treating tumors that do not express molecular targets of immune checkpoint inhibitors and are resistant to immune checkpoint inhibitors. Enhancement of the anti-cancer activity of antigen-specific T cell infusions can be obtained by using an antigen-loaded nanogel that contains a hydrophobized polysaccharide-based nanogel as the delivery system, and a synthetic long chain peptide antigen or a recombinant protein antigen and an immune-enhancing agent as a pretreatment drug.

[0037]FIG. 1 shows data indicating the expression of PD-L1 and PD-1, and the numbers of tumor-infiltrating CD8+ T cells for various mouse tumors implanted subcutaneously and engrafted into BALB/c mice. (A) is a photomicrograph showing the results of analyzing the expression of PD-L1 molecules in tumors locally after 7 days from being implanted, (B) is a graph showing the results of analyzing the PD-1 expression of CD3+ T cells localized in each tumor by flow cytometry, and (C) is a graph showing the results of the analysis of the number of CD8+ T cells that infiltrated into each tumor.

[0038]FIG. 2 depicts graphs showing the results of examining the susceptibility to immune checkpoint inhibitors of various mouse tumors implanted subcutaneously and engrafted into BALB/c mice.

[0039]FIG. 3 depicts graphs showing the results of the therapeutic efficacy of antigen-specific T cell infusion on BALB/c mice that were subcutaneously transplanted with fibrosarcoma CMS5a tumors using a pretreatment drug that contains a long chain peptide antigen-loaded cholesteryl pullulan (CHP) nanogel and an immune-enhancing agent. (A) is a graph showing that antigen-specific T cell infusion after subcutaneous administration of the long chain peptide antigen-loaded CHP nanogel and CpG oligo DNA can heal CMS5a tumors, and that incomplete Freund's adjuvant (IFA), instead of the nanogel as the delivery system, can not heal CMS5a tumors, (B) is a graph showing th

Problems solved by technology

Development of effective treatments for cancer patients who are resistant to immune checkpoint inhibitors has become an important issue in cancer

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