T cell migration and cardiovascular toxicity in immunotherapy

免疫治疗中的 T 细胞迁移和心血管毒性

基本信息

批准号：
10646491
负责人：
Minsoo Kim
金额：
$ 56.94万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-22 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646491
关键词：
Address Adhesions Adoptive Cell Transfers Adoptive Transfer Atherosclerosis Autoimmune Diseases Autologous Blast Cell Blood Blood Vessels CD8-Positive T-Lymphocytes Cardiovascular system Cell Adhesion Cells Cellular Assay Chemicals Circulation Clinical Cytoskeletal Proteins Cytoskeleton Cytotoxic T-Lymphocytes Data Dependence Disease Down-Regulation Effectiveness Endosomes Genetic Engineering Hematologic Neoplasms Homing Immunotherapy Impairment In Vitro Inflammatory Inflammatory Response Integrins Intercellular adhesion molecule 1 Intravenous Knowledge Learning Lung Malignant Neoplasms Mediating Mediator Microcirculation Modification Molecular Mus Pathology Patients Pattern Pertussis Toxin Probability Property Proteins Recycling Regulation Resolution Risk Safety Site Solid Neoplasm Spectrin T cell regulation T cell therapy T-Cell Activation T-Lymphocyte Techniques Testing Therapeutic Tissues Toxic effect Virus Diseases anti-cancer cancer therapy cardiovascular risk factor cell motility chemokine chimeric antigen receptor T cells cytokine release syndrome cytotoxicity effector T cell engineered T cells hazard hemodynamics improved in vivo inhibitor knock-down manufacture manufacturing cost manufacturing process mechanical properties migration mouse model multiphoton imaging novel optogenetics prevent rab GTP-Binding Proteins response screening side effect success systemic inflammatory response therapy outcome trafficking tumor

项目摘要

PROJECT SUMMARY/ABSTRACT T cell immunotherapy is emerging as a promising cancer treatment option and has proven effective in a range of malignancy. However, a concern has been that prolong circulation and/or non-specific migration of the adoptively transferred in vitro activated T cells to non-target tissue sites might predispose to cardiovascular damages and systemic inflammatory responses. Anecdotal evidence of a cardiovascular hazard has emerged and abundant data point to exacerbation of cytokine release syndrome associated with T cell immunotherapy. We undertook this study to address critical knowledge gaps regarding the molecular mechanisms that determine the function and fate of the adoptively transferred in vitro-generated T cells, and cardiovascular toxicity associated with sequestration of the therapeutic T cells at non-tumor-bearing tissues after intravenous transfer. Through several lines of evidence from our preliminary study, we propose that autologous T cells undergo significant molecular and cellular reprogramming during ex-vivo manufacturing process. We predict that the intrinsic changes are important for the robust T cell activation and expansion, but fail to derive T cell migration toward the target tumor, and thus serve to increase toxicity. We discovered that a decrease in βII-spectrin expression during in vitro T cell activation results in decreased cell stiffness and a dramatic change in spontaneous T cell migration pattern upon intravenous transfer. Moreover, screening of a key intracellular protein associated with the altered T cell migration revealed a novel Rab13-mediated endosomal redistribution pattern that mediates the non-specific T cell migration. We will, (1) determine the causes of cardiovascular cytotoxicity and cytokine release syndrome associated with non-specific migration of in vitro activated T cells, (2) determine the molecular mechanisms that prevent specific migration toward the target tissue site, and (3) test whether we can generate T cells with an improved tissue-specific homing property and a reduced cardiovascular side-effects. These studies will combine differential perturbations of novel mechanisms that regulate activated T cell migration, in vivo mouse models, state of the art intravital multiphoton imaging, high-resolution singles cell assays, and analysis defining vascular inflammatory responses to understand a potentially serious risk of adoptively T cell transfer immunotherapy. We shall also explore novel alternative approaches that might promote the anti-cancer efficacy and minimize the cardiovascular risk of the T cell immunotherapy.

项目概要/摘要 T 细胞免疫疗法正在成为一种有前途的癌症治疗选择，并已被证明在一系列范围内有效然而，人们担心的是，细胞的循环和/或非特异性迁移会延长。将体外活化的 T 细胞过继转移至非靶组织部位可能会导致心血管疾病损害和全身炎症反应的证据已经出现。大量数据表明与 T 细胞免疫治疗相关的细胞因子释放综合征会加剧。我们进行这项研究是为了解决有关决定的分子机制的关键知识差距过继转移的体外生成的 T 细胞的功能和命运以及心血管毒性与静脉转移后治疗性 T 细胞在非肿瘤组织中的隔离有关。通过我们初步研究的几条证据，我们建议自体 T 细胞经历我们预测在离体制造过程中会发生显着的分子和细胞重编程。内在变化对于 T 细胞的强大激活和扩增很重要，但无法衍生 T 细胞迁移我们发现βII-血影蛋白减少。体外 T 细胞激活过程中的表达导致细胞硬度降低和静脉转移后的自发 T 细胞迁移模式此外，筛选关键的细胞内蛋白质。与 T 细胞迁移改变相关的揭示了一种新的 Rab13 介导的内体重新分布模式我们将：(1) 确定心血管细胞毒性的原因。和与体外活化 T 细胞非特异性迁移相关的细胞因子释放综合征，(2) 确定阻止向目标组织部位特异性迁移的分子机制，以及（3）测试我们是否可以产生具有改善的组织特异性归巢特性并减少心血管副作用的 T 细胞。这些研究将结合调节活化 T 细胞的新机制的差异扰动迁移，体内小鼠模型，最先进的活体多光子成像，高分辨率单细胞定义血管炎症反应的测定和分析，以了解潜在的严重风险我们还将探索可能促进 T 细胞转移免疫疗法的新替代方法。 T 细胞免疫疗法的抗癌功效并最大限度地降低心血管风险。