Chimeric Antigen Receptor (CAR) Directed T-regulatory Cell Therapy for Aortic Aneurysm

嵌合抗原受体 (CAR) 定向 T 调节细胞治疗主动脉瘤

• 批准号: 10375495
• 负责人: Adam Oskowitz
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375495
• 关键词: Abdominal Aortic Aneurysm; Adoptive Transfer; Affinity; Aneurysm; Animal Model; Aortic Aneurysm; Aortic Injury; Area; Autoimmune; Autoimmune Diseases; Binding; Blood Vessels; CD28 gene; Cardiovascular Diseases; Cause of Death; Cell Therapy; Cell surface; Cells; Cellular biology; Cessation of life; Chimeric Proteins; Chronic; Clinical; Complementary DNA; Developed Countries; Development; Disease; Effectiveness; Elastin; Elastin Fiber; Engineering; Epitopes; Extracellular Domain; Extracellular Matrix; Generations; Goals; Growth; Growth and Development function; Homing; Human; Immune response; Immunosuppression; In Vitro; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Lead; Location; Mediating; Medical; Methods; Morbidity - disease rate; Operative Surgical Procedures; Patients; Play; Population; Precision therapeutics; Process; Receptor Activation; Regulatory T-Lymphocyte; Research; Resolution; Risk; Rodent Model; Role; Rupture; Ruptured Abdominal Aortic Aneurysm; Signal Transduction; Specificity; Sterility; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Translating; Transmembrane Domain; Transplantation; Work; antigen binding; base; cell injury; chimeric antigen receptor; early phase clinical trial; efficacy testing; elastin-binding protein; experience; extracellular; high reward; high risk; human subject; immunoregulation; innovation; insight; mortality; novel; novel strategies; novel therapeutics; preclinical trial; prevent; receptor; response; side effect; targeted treatment; tool; vascular inflammation; vector

Project Summary/Abstract The objective of the proposed research is to develop a precision T-regulatory cell (Treg)-based treatment to prevent growth and rupture of abdominal aortic aneurysms (AAA), a leading cause of death in developed countries. AAA result from uncontrolled inflammation.Thus, modulation of aortic specific inflammation could lead to the development of medical treatment for AAA, thereby delaying or preventing the need for surgical intervention and ultimately removing the risk of aneurysm-related death. Tregs are vital in preventing autoimmune diseases and promoting resolution of immune response. Recently, Chimeric Antigen Receptors (CARs) have been used to generate precision therapy by directing T-cells to bind and activate at specific locations within the body. We therefore hypothesize that we can engineer a CAR to be expressed in Tregs that will direct them to bind to damaged aortic tissue and block the inflammatory process. Elastin Binding Protein (EBP) is an endogenous receptor that directs inflammatory cells to damaged aortic tissue in humans. Consequently, EBP is an ideal candidate to direct Tregs to damaged aortic tissue in AAA patients as a key component of a CAR. Our team has significant experience studying vascular inflammation, AAA, and Treg biology, and has successfully engineered CARs in the past. Based on our collective expertise we propose to investigate two Specific Aims to characterize the interaction of Tregs and damaged aortic tissue and generate an engineered Treg to be used to treat AAA: Aim 1: Genetically modify Tregs to express an EBP- CAR that targets damaged elastin in aortic tissue. Aim 2: Evaluate the binding capacity and activation of Tregs and genetically modified Tregs to aortic tissue from patients with aortic aneurysms. We believe these studies will allow us to gain a more in-depth understanding of the interaction between Tregs and damaged aortic tissue, while developing an innovative strategy to oppose vascular inflammation. If successful, this work will allow us to generate a CAR-Treg that can be tested for efficacy in animal models of AAA and potentially be translated into a novel therapeutic tool for the treatment of AAA, a disease that currently lacks effective medical treatment options. ! !

项目总结/摘要 这项研究的目的是开发一种精确的基于T调节细胞（Treg）的治疗方法， 防止腹主动脉瘤（AAA）的生长和破裂，腹主动脉瘤是发达国家死亡的主要原因 国家AAA是由不受控制的炎症引起的。因此，调节主动脉特异性炎症可以 导致AAA的医学治疗的发展，从而延迟或防止手术的需要。 干预，并最终消除与药物相关的死亡风险。 免疫球蛋白在预防自身免疫性疾病和促进免疫反应的解决方面至关重要。最近， 嵌合抗原受体（汽车）已被用于通过引导T细胞与靶向T细胞结合来产生精确治疗。 并在体内的特定位置激活。因此，我们假设我们可以设计一辆汽车， 在TcB中表达，这将引导它们结合到受损的主动脉组织并阻断炎症过程。 弹性蛋白结合蛋白（EBP）是一种内源性受体，可将炎症细胞导向受损的主动脉 人体组织因此，EBP是一种理想的候选者，可将THBE引导至AAA中受损的主动脉组织 患者作为CAR的关键组成部分。我们的团队在研究血管炎症方面有丰富的经验， AAA和Treg生物学，并在过去成功地设计了汽车。基于我们的专业知识 我们建议研究两个特定的目标，以表征TdR和受损主动脉组织的相互作用 并产生用于治疗AAA的工程化Treg：目的1：遗传修饰Treg以表达EBP-1。 CAR靶向主动脉组织中受损的弹性蛋白。目的2：评价TdR的结合能力和活化 和基因改造的THBE到主动脉瘤患者的主动脉组织中。 我们相信这些研究将使我们更深入地了解TdR之间的相互作用， 和受损的主动脉组织，同时开发一种创新的策略来对抗血管炎症。如果 如果成功，这项工作将使我们能够产生一种CAR-Treg，可以在动物模型中测试其功效。 AAA，并有可能被转化为一种新的治疗工具，用于治疗AAA，这种疾病， 目前缺乏有效的治疗方案。 ! !