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

a technology of immune checkpoint inhibitor and infusion therapy, which is applied in the field of pretreatment drugs, can solve the problems that tumor therapy may be less effective, and achieve the effect of improving the anti-cancer activity of antigen-specific t cell infusions

Inactive Publication Date: 2019-04-18
MIE UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides pharmaceutical compositions for treating tumors that do not express molecular targets of immune checkpoint inhibitors and are resistant to immune checkpoint inhibitors. The compositions include an antigen-loaded nanogel containing a hydrophobized polysaccharide-based nanogel as a delivery system and a synthetic long chain peptide antigen or a recombinant protein antigen and an immune-enhancing agent as a pretreatment drug. The use of these compositions can enhance the anti-cancer activity of antigen-specific T cell infusions and improve the immunotherapy of tumors.

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 treatment.
However, these therapies may be less effective against tumors that do not express the molecular targets of immune checkpoint inhibitors.

Method used

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

Examples

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example 1

[0064]1. Materials and Methods

[0065]Anti-mouse CD16 / CD32 antibody (clone 93), PE-labeled anti-mouse PD-L1 antibody (clone 9G2), APC-Cy7-labeled anti-CD45 antibody (clone 30-F11), and PE-Cy7-labeled anti-PD-1 antibody (clone 29F.1A12) were purchased from Biolegend. V450-labeled anti-CD8 antibody (clone 53-6.7) was purchased from eBioscience. Fetal bovine serum (FBS) was purchased from Bio-West. RPMI1640 medium (containing 2-mercaptoethanol) was purchased from the Cell Science Institute. Erythrocyte hemolysis solution (0.15 M NH4Cl / 10 mM KHCO3 / 0.1 mM EDTA.Na2 pH 7.2) was prepared at Mie University. Mouse colon cancer CT26 cell line (CRL-2638) was purchased from ATCC and was used as subcultured at Mie University. Mouse fibrosarcoma CMS7 cell line and murine fibrosarcoma CMS5a cell line were obtained from Memorial Sloan-Kettering Cancer Institute and were used as subcultured at Mie University. Human NY-ESO-1 antigen gene was obtained from Memorial Sloan-Kettering Cancer Institute. CMS5a...

example 2

[0071]1. Materials and Methods

[0072]A hybridoma that expresses anti-mouse CTLA-4 antibody (clone 9D9) was obtained from Dr. James P. Allison at the MD Anderson Cancer Center, and antibody was prepared at Mie University. A hybridoma that expresses anti-mouse GITR antibody (clone DTA-1) was obtained from Dr. Shimon Sakaguchi at Osaka University, and antibody was prepared at Mie University. Anti-mouse-PD-1 antibody (clone RMP1-14) was obtained from Dr. Hideo Yagita at Juntendo University. Fetal bovine serum (FBS) was purchased from Bio-West. RPMI1640 medium (containing 2-mercaptoethanol) was purchased from the Cell Science Institute. Mouse colon cancer CT26 cell line (CRL-2638) was purchased from ATCC and was used as subcultured at Mie University. Mouse fibrosarcoma CMS7 cell line and murine fibrosarcoma CMS5a cell line were obtained from Memorial Sloan-Kettering Cancer Institute and were used as subcultured at Mie University. Human NY-ESO-1 antigen gene was obtained from Memorial Sloa...

example 3

[0076]1. Materials and Methods

[0077]Cholesteryl pullulan (abbreviation CHP, trade name CHP-80T) was obtained from NOF Corporation. Incomplete Freund's adjuvant (abbreviation IFA, product number F5506) was purchased from Sigma-Aldrich. Long chain peptide antigen-loaded CHP nanogel was prepared as follows. Long peptides antigens (MEN peptide: SNPARYEFLYYYYYYQYIHSANVLYYYYYYRGPESRLL (SEQ ID NO: 1) and p121 peptide: NDHIAYFLYQILRGLQYIHSANVLHRDLKPSNLLLNT (SEQ ID NO: 2)) were chemically synthesized by Bio-Synthesis and were dissolved in dimethyl sulfoxide (abbreviation DMSO, Nacalai Tesque) at a concentration of 10 mg / mL. CHP was dissolved in phosphate-buffered saline (PBS) containing 6 M urea (Nacalai Tesque) at a concentration of 10 mg / mL. One mL (10 mg) of the long chain peptide antigen solution and 20 mL (200 mg) of the CHP solution were mixed and left overnight with gentle stirring at 4° C. in the dark. The mixture was transferred to a dialysis membrane (molecular weight: 3,500, Therm...

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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...

Claims

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Application Information

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IPC IPC(8): A61K35/17A61K39/00A61K45/00A61K47/36A61K9/14C07K14/00
CPCA61K35/17A61K39/00A61K45/00A61K47/36A61K9/14C07K14/00A61K45/06A61K9/5161A61K9/0019A01K2267/0331A01K2227/105A01K2207/12A61P35/00A61K2239/31A61K39/4611A61K39/464462A61K39/4632A01K67/027
Inventor SHIKU, HIROSHIHARADA, NAOZUMIMURAOKA, DAISUKEAKIYOSHI, KAZUNARI
Owner MIE UNIVERSITY
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