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Class II artificial antigen presenting cells for cancer immunotherapy

用于癌症免疫治疗的 II 类人工抗原呈递细胞

基本信息

批准号：
10156950
负责人：
Ariel Yosef Isser
金额：
$ 4.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-19 至 2023-07-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156950
关键词：
Adoptive Cell Transfers Adoptive Transfer Antigen-Presenting Cells Antigens Autoantigens Autologous Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CTAG1 gene Cancer Patient Cell Lineage Cell physiology Cells Clinical DR1 gene Dendritic Cells Engineering Epitopes Goals Histocompatibility Antigens Class II Human Human Cell Line Immune response Immunotherapy In Vitro Influenza A virus Iron-Dextran Complex Link MEL Gene Malignant Neoplasms Melanoma Cell Memory Methods Modeling Monitor Mus Output Ovalbumin Patients Peptides Phase Phase I Clinical Trials Population Proteins Protocols documentation Recovery Reporting Research Role Site Solid Neoplasm Stains T-Cell Receptor T-Lymphocyte Technology Thrombin Time Transgenic Mice Transgenic Organisms Tumor Antigens Tumor Cell Line Tumor Expansion Tumor-Infiltrating Lymphocytes Tyrosinase related protein-1 alpha-Thrombin anti-tumor immune response antigen-specific T cells base cancer cell cancer immunotherapy cancer therapy clinical translation clinically relevant cost cytokine cytotoxic CD8 T cells experimental study in vivo insight melanoma nanoparticle novel pre-clinical protein complex response synergism transcription factor tumor

项目摘要

Project Summary Adoptive cell therapy (ACT) has become an increasingly attractive method for treating patients with solid tumors due to its impressive response rate; that said, the costs and complexity of current cellular approaches for expansion of tumor-specific T cells have limited accessibility of this therapy. Significant progress has been made in scalable, acellular technologies for expanding tumor-specific CD8 T cells. However, no analogous acellular platforms for expansion of CD4 T cells exist, despite overwhelming preclinical and clinical evidence that CD4 T cells are central to antitumor immune responses and can augment CD8- based therapies. The goal of the proposed project is to investigate the application of a novel Class II artificial antigen presenting cell (aAPC) for expansion of functional, polyclonal endogenous tumor-specific CD4 T cells for ACT as well as potential synergies with endogenous CD8 T cells. The platform, which consists of a 50 nm paramagnetic iron dextran nanoparticle conjugated with Class II Major Histocompatibility Complex proteins and costimulatory molecules, will allow us 1) to enrich and expand rare murine and human tumor-specific CD4 T cells to clinically relevant levels, and 2) to facilitate dendritic cell (DC) independent T cell help. In turn, the Class II aAPC will allow us for the first time to monitor both the antitumor efficacy and T cell receptor dynamics of ACT with polyclonal CD4 or combined CD4 and CD8 T cells in mice. To accomplish these goals, the project will proceed in three phases. First, we will investigate the in vitro function and in vivo antitumor efficacy of aAPC-expanded polyclonal CD4 T cells specific to foreign and self-antigens, OVA and Trp1 with B16-OVA and B16-F10 melanoma models, respectively. Second, we will apply a modular human Class II aAPC, capable of expanding a range of antigen-specific CD4 T cells through HLA molecules loaded with thrombin-cleavable peptides, to expand functional tumor-antigen NY-ESO-1 specific CD4 T cells from HLA DR1 and DP4 donors. Finally, we will combine the Class I and Class II aAPC technologies to investigate DC independent in vitro and in vivo antitumor synergies of combined antigen-specific mouse and human CD4 and CD8 culture, using B16-OVA and B16-F10 for mouse T cells, and the human SK-MEL-37 (A2+/NY-ESO-1+) melanoma cell line for human T cells. If successful, this proposal will deliver a novel acellular approach for polyclonal CD4 or combined CD4 and CD8 ACT and will provide insight into alternative mechanisms of T cell help, with potential clinical ramifications for ex vivo CD8 T cell expansion.

项目总结