Engineering 2nd generation 5MCARs to monitor and treat Type-I Diabetes

设计第二代 5MCAR 来监测和治疗 I 型糖尿病

基本信息

批准号：
10598106
负责人：
Michael S Kuhns
金额：
$ 83.11万
依托单位：
UNIVERSITY OF ARIZONA
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/10598106
关键词：
Antibodies Antigens Area Autoimmune Autoimmune Diabetes Autoimmune Diseases Beta Cell Biological Markers Biomimetics Blood CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD8B1 gene Cells Cellular immunotherapy Clinic Clinical Complex Cytoprotection Cytotoxic T-Lymphocytes Data Detection Development Diabetes Mellitus Disease E protein Elements Engineering Environment Event Evolution Foundations Generations Goals Health Home Human Immune In Vitro Inbred NOD Mice Incidence Insulin-Dependent Diabetes Mellitus Investigation Knowledge Lead Mediating Memory Modification Molecular Monitor Mus Pancreas Pathogenicity Peptides Performance Phenotype Population Positioning Attribute Pre-Clinical Model Prevention Process Publishing Regulatory T-Lymphocyte Reporter Reporting Safety Sentinel Signal Transduction Solid Symptoms T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tissues Transmembrane Domain Work alpha-Fetoproteins autoreactive T cell beta-2 Microglobulin biomarker driven cellular engineering chimeric antigen receptor chimeric antigen receptor T cells clinical application design functional improvement immunoengineering improved in vivo infancy innovation insulitis islet mouse model new technology novel pre-clinical prevent receptor research clinical testing response sensor stem cells trafficking treatment response

项目摘要

PROJECT SUMMARY This proposal is aimed at developing immune cell engineering approaches for the monitoring and treatment of T cell-mediated autoimmune diseases such as Type-I diabetes (T1D). The native 5-module receptor complexes that drive T cell responses to peptide antigens embedded in MHC molecules have evolved through an iterative process over the last ~435 million years to optimize T cell responses to a broad range of challenges. Using a biomimetic approach, we have developed a 5-module chimeric antigen receptor (5MCAR) and reported that cytotoxic T cells expressing 5MCARs (5MCAR-CTLs) can specifically target and kill autoimmune CD4+ T cells that mediate T1D in preclinical mouse models, resulting in significantly reduced disease incidence in 5MCAR-CTL-treated mice. Our proof-of-concept work supports the idea, echoed by the RFA to which we are responding, that engineered immune cell-based immunotherapies hold promise for the treatment of autoimmune diseases. Also as noted in the RFA, this area of investigation is in its infancy and requires support of exploratory engineering approaches to reach its full potential. Our foundational work provides us with a novel platform from which to continue the development of novel biomimetic engineering approaches for detecting and eliminating autoimmune T cell responses. Our goals here will be to develop novel applications using our 1st generation 5MCAR technology and to iterate on the 5MCAR platform through the engineering and testing of 2nd generation 5MCARs. Specifically, we will: 1) determine if using 5MCARs to redirect central memory CD8+ T cells, stem cell memory CD8+ T cells, or Tregs are most effective at preventing T1D in preclinical models; 2) use 5MCAR-CTLs as sentinels that can trafficking throughout the body and report on the presence of pathogenic autoimmune CD4+ T cells prior to clinical symptoms; and, 3) engineer and test 2nd generation 5MCARs that more closely mimic their native counterparts with the goal of improving 5MCAR performance. When completed, the proposed work will provide valuable pre-clinical data for the therapeutic potential of biomimetic 5MCAR-CTLs and 5MCAR-Tregs that are engineered based on evolution’s blueprint.