Engineered Immune Cells for T1D

针对 T1D 的工程化免疫细胞

基本信息

批准号：
10595044
负责人：
EVERETT MEYER
金额：
$ 77.88万
依托单位：
STANFORD UNIVERSITY
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：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595044
关键词：
Adult Antigen Targeting Antigen-Presenting Cells Antigens Apoptosis Area Autoantigens Autoimmunity Autologous B-Lymphocytes Beta Cell Biology Cell Death Cell Survival Cell Therapy Cell physiology Cell surface Cells Childhood Clinical Clinical Trials Cytoprotection Data Defect Development Diagnosis Disease Effectiveness Engineering FDA approved FOXP3 gene Foundations Gene Expression Genes Genetic Engineering Goals Health Heparin Lyase Homing Human IL2RA gene Immune Immune Tolerance Immune mediated destruction Immunology Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Incidence Individual Inflammatory Infusion procedures Insulin-Dependent Diabetes Mellitus Investigation Islets of Langerhans Malignant Neoplasms Measures Mediating Metabolic stress Methods Modeling Mus Myelogenous Myeloid Cells Natural regeneration Newly Diagnosed Pathogenicity Patients Performance Phase Phenotype Population Pre-Clinical Model Protein Engineering Regulatory T-Lymphocyte Request for Proposals Research Personnel Signal Transduction Signaling Molecule Specificity Structure of beta Cell of islet Surface Surface Antigens System T-Cell Receptor T-Lymphocyte Testing Therapeutic Xenograft procedure allograft rejection autoimmune pathogenesis biobank biological adaptation to stress cancer cell cell type cellular engineering cellular targeting chimeric antigen receptor cytotoxic extracellular high risk immunoengineering immunoregulation improved in vivo insulin dependent diabetes mellitus onset islet islet allograft monocyte novel novel therapeutics overexpression preservation prevent response stress reduction therapeutic target

项目摘要

Project Summary / Abstract This application is in response to a specific request for proposals to develop immune cell engineering towards the treatment of type 1 diabetes (T1D). We propose to evaluate genetic engineering approaches in immune T regulatory cells (Treg) by integrating chimeric antigen receptor (CAR) proteins that are engineered with an external targeting domain (scFv) and internal stimulatory domain. This approach has revolutionized cancer cell therapy with heightened specificity and effectiveness of T cell action. We and others have found evidence that CAR Treg can help mediate immune protection of islets and may even act upon islets themselves to reduce stress and cell death. We propose to (a) determine how enhanced targeting and activation of Treg to human islets might improve islet function and local immune modulation to protect islets, (b) evaluate a method for enhanced islet targeting through the development and testing of a dual-targeting CAR system that exploits downstream T cell receptor signaling molecules that have not been previously evaluated and (c) determine how enhanced targeting and activation of Treg to human monocytes might result in more immunoregulatory monocytes that could help to alter response to islet autoantigens and prevent immune destruction. One very important component of our proposal is that we suspect that CAR Treg from patients with T1D may not function as well as CAR Treg from normal individuals. In fact, there is no data about this available. We think that some CAR Treg from some T1D patients might be more cytotoxic, less effective or more inflammatory and we propose to evaluate if this is true statistically and also to develop an approach to introduce and overexpress a set of genes known to be important for Treg function as a way of making sure that all Treg in all cases will exert effects that are wanted. We postulate that developing these Treg methods will produce novel clinical strategies to prevent T1D in high risk patients and to suppress autoimmunity and preserve β-cell mass in patients with recent-onset T1D.

项目概要/摘要该申请是为了响应针对开发免疫细胞工程的提案的具体要求我们建议评估免疫 T 的基因工程方法。通过整合嵌合抗原受体（CAR）蛋白来调节细胞（Treg）外部靶向结构域（scFv）和内部刺激结构域彻底改变了癌细胞。我们和其他人已经发现了具有尿液特异性和 T 细胞作用有效性的治疗。 CAR Treg 可以帮助介导胰岛的免疫保护，甚至可以作用于胰岛本身以减少我们建议 (a) 确定如何增强 Treg 对人类的靶向和激活。胰岛可能会改善胰岛功能和局部免疫调节以保护胰岛，（b）评估一种方法通过开发和测试双靶向 CAR 系统来增强胰岛靶向，该系统利用之前未评估过的下游 T 细胞受体信号分子，并且 (c) 确定增强 Treg 对人类单核细胞的靶向和激活如何可能导致更多的免疫调节单核细胞可以帮助改变对胰岛自身抗原的反应并防止免疫破坏。我们提案的重要组成部分是我们怀疑来自 T1D 患者的 CAR Treg 可能不会功能以及正常个体的 CAR Treg 事实上，我们认为没有这方面的数据。来自一些 T1D 患者的一些 CAR Treg 可能具有更高的细胞毒性、效果较差或更具炎症性，我们建议评估这在统计上是否属实，并开发一种引入和过度表达的方法一组已知对 Treg 功能很重要的基因，以确保所有情况下的所有 Treg 都会我们假设开发这些 Treg 方法将产生临床新颖的效果。预防高危患者 T1D 以及抑制自身免疫和保护 β 细胞量的策略近期发病的 T1D 患者。