Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands

使用 CAR 和肽-MHC 嵌合抗原配体精确靶向 T1D 特异性 T 细胞

基本信息

批准号：
10621960
负责人：
Michael Birnbaum
金额：
$ 67.46万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621960
关键词：
Address Affinity Animal Model Antigen Targeting Antigens Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity Beta Cell Binding Biological Models Blood Glucose CAR T cell therapy Cell Separation Cell Therapy Cells Clinical Collaborations Collection Core Facility Data Diabetic mouse Engineering Epitopes Experimental Designs Failure Future Goals Hematologic Neoplasms Hematopoietic Neoplasms Human Human Cloning Immune Targeting Immune mediated destruction Immune system Immunology Immunosuppression In Vitro Insulin-Dependent Diabetes Mellitus Islet Cell Ligands Maps Memory Modeling Mus Outcome Patients Peptide/MHC Complex Peptides Performance Reagent Signal Transduction Source Specificity Specimen Structure System T cell infiltration T-Lymphocyte Techniques Technology Testing Work antigen binding autoreactive T cell autoreactivity cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy clinical implementation design exhaustion experimental study flexibility humanized mouse improved in vitro Assay in vivo islet novel prevent recruit standard care synthetic biology

项目摘要

Project Summary Type 1 diabetes (T1D) is an incurable autoimmune disease manifested through the immune destruction of islet beta cells. This proposal describes a unique CAR T cell approach to eliminate islet-autoreactive T cells, thus eliminating the source of the autoimmunity and providing a highly specific treatment for T1D. We will leverage our recently developed split CAR system with a chimeric antigen ligand (CAL) adaptor consisting of a pMHC multimer fused to a recruitment molecule. The addition of CAL will bind to the autoreactive TCR and recruit the universal CAR T cells to kill autoreactive T1D specific T cells. The proposed experiments will test the hypoth- eses that (1) our modular CAR/CAL systems are uniquely suited for specifically targeting multiple auto- reactive TCRs, and (2) that we can identify novel epitopes against T1D specific TCRs to be paired with the CAR/CAL system. Importantly, preliminary data support these hypotheses, and well-characterized clinical specimens from T1D patients and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise that encompass synthetic biology, large-scale epitope discovery, T1D immunology, and humanized T1D animal modeling. The specific aims of this five-year proposal are as follows: Aim 1 establish and optimize the CAL system against antigen-specific human TCRs, Aim 2 characterize the autoreactivity of TCRs from T1D patients/donors and identify peptide-MHC against these TCRs, and Aim 3 evaluate the performance of the CAL system in humanized T1D animal models. Outcomes from this work will establish the clinical potential of the CAR/CAL system as a safe, effective, and potentially curative T1D treatment.

项目概要 1型糖尿病（T1D）是一种无法治愈的自身免疫性疾病，表现为胰岛的免疫破坏 β细胞。该提案描述了一种独特的 CAR T 细胞方法来消除胰岛自身反应性 T 细胞，从而消除自身免疫源并为 T1D 提供高度特异性的治疗。我们将利用我们最近开发的拆分 CAR 系统，带有由 pMHC 组成的嵌合抗原配体 (CAL) 接头与招募分子融合的多聚体。添加 CAL 将与自身反应性 TCR 结合并招募通用 CAR T 细胞可杀死自身反应性 T1D 特异性 T 细胞。拟议的实验将检验假设 (1) 我们的模块化 CAR/CAL 系统特别适合专门针对多个自动反应性 TCR，以及 (2) 我们可以识别针对 T1D 特异性 TCR 的新表位以与之配对 CAR/CAL 系统。重要的是，初步数据支持这些假设，并且充分表征的临床该提案建立了来自 T1D 患者的标本和严格的实验设计，并具有必要的跨学科合作和专业知识，包括合成生物学、大规模表位发现、 T1D 免疫学和人性化 T1D 动物模型。该五年提案的具体目标是目标 1 建立并优化针对抗原特异性人类 TCR 的 CAL 系统，目标 2 表征 T1D 患者/捐赠者的 TCR 自身反应性，并针对这些 TCR 识别肽-MHC，以及目标 3 评估 CAL 系统在人源化 T1D 动物模型中的性能。这项工作的成果将确定 CAR/CAL 系统作为安全、有效且具有潜在治愈性 T1D 治疗方法的临床潜力。