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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.

项目总结/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领域有效。恶性肿瘤然而，令人担忧的是，过继转移体外活化T细胞到非靶组织部位可能易患心血管疾病，损伤和全身炎症反应。关于心血管危害的传闻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的恶化。我们进行这项研究，以解决关键的知识差距有关的分子机制，决定过继转移的体外产生的T细胞的功能和命运，以及心血管毒性这与静脉内转移后治疗性T细胞在非携带肿瘤的组织处的隔离有关。通过我们初步研究的几条证据，我们提出自体T细胞经历了在离体制造过程中显著的分子和细胞重编程。我们预测内在变化对于T细胞的活化和扩增是重要的，但不能导致T细胞迁移向靶肿瘤转移，从而增加毒性。我们发现β II-血影蛋白的减少在体外T细胞活化过程中的表达导致细胞硬度降低，并且在细胞内表达的显著变化。静脉内转移后自发T细胞迁移模式。此外，筛选关键的细胞内蛋白质与改变的T细胞迁移相关，揭示了一种新的Rab 13介导的内体再分布模式介导非特异性T细胞迁移。我们将，（1）确定心血管细胞毒性的原因和与体外活化T细胞的非特异性迁移相关的细胞因子释放综合征，（2）确定阻止向靶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和降低的心血管副作用的T细胞。这些研究将结合联合收割机调节活化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，高分辨率单细胞测定和分析定义血管炎症反应，以了解潜在的严重风险，过继性T细胞转移免疫疗法。我们还将探索新的替代方法，抗癌功效和最小化T细胞免疫疗法的心血管风险。