Development of senolytic CAR T cells as new therapeutic agents

开发 senolytic CAR T 细胞作为新的治疗剂

基本信息

批准号：
10221652
负责人：
Corina Amor Vegas
金额：
$ 4.6万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221652
关键词：
Alzheimer&apos s Disease Antigens Atherosclerosis B-Lymphocytes BCL2 gene Biological CD19 gene Cell Aging Cell Cycle Cell Cycle Arrest Cell Therapy Cell surface Cells Chemicals Chronic Chronic Disease Clinical Collaborations Data Development Diabetes Mellitus Disease Dose-Limiting Enzymes Extracellular Matrix Functional disorder Goals Hematologic Neoplasms Heterogeneity Homeostasis Immunologic Surveillance In Vitro Inflammatory Knowledge Laboratories Letters Light Liver Fibrosis Malignant Neoplasms Mediating Membrane Proteins Modeling Mus Pathologic Pathology Patients Phenotype Physiological Pleural effusion disorder Premalignant Cell Proteins Pulmonary Fibrosis Quercetin Refractory Research Research Project Grants Rest Role Safety Solid Neoplasm Stress Surface Surface Antigens T-Lymphocyte Technology Testing Therapeutic Therapeutic Agents Thrombocytopenia Time Tissues Toxic effect Tumor Burden Work age related associated symptom base biological adaptation to stress cancer therapy cellular engineering chemokine chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical development combinatorial cytokine efficacy testing genetic approach immune clearance improved in vitro testing in vivo inflammatory milieu inhibitor/antagonist irradiation novel therapeutics pre-clinical preclinical study preconditioning prevent programs receptor reduce symptoms response restoration senescence side effect stressor success trafficking transcriptome sequencing tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Senescence is a cellular program that leads to irreversible cell cycle arrest in response to stress. Although in the short term it promotes restoration of tissue homeostasis, the lack of immune clearance of senescent cells and thus their chronic accumulation leads to a chronic pro-inflammatory environment that has been shown to promote tumor development and to contribute to a variety of pathologies associated with chronic tissue damage such as lung or liver fibrosis, diabetes and atherosclerosis among others. Previous senolytic approaches have relied on the use of non-selective chemical inhibitors that have off-target toxicities and, owing to heterogeneity between senescent cells, are inefficient. The long term objective of my thesis project is to develop, for the first time, Chimeric Antigen Receptor (CAR) T cells as living senolytic agents. As a first step towards developing senolytic CAR T we will identify senescence-specific surface molecules to better identify, characterize and target senescent cells. In parallel, we will exploit the selective features of these molecules with the aim of producing senolytic CAR T cells, which we then characterize their efficacy and safety profile in preclinical senescence models. Preliminary data from the initial years of my graduate studies strongly supports the feasibility of the proposed work: we have already identified one cell surface molecule predominantly expressed on senescent cells and developed CAR T cells targeting it. We further provide preliminary data showing that these CAR T cells are bona fide senolytics capable of eliminating senescent cells in culture and in mice. For the rest of my doctoral work we continue to validate the protein and senolytic CAR T cells and gain better understanding of their mechanism of action and safety profile and use our findings to develop enhanced versions as well as combinatorial targeting strategies with newly identified factors. Completion of the proposed work will lead to the development of effective senolytic CAR T cells and provide further data for their clinical development as novel therapeutic options in cancer as well as for a wide range of other senescence- associated diseases. My postdoctoral research will continue to study senescence and CAR T cells but with a slight change of focus in order to try to understand how the Senescence Associated Secretory Phenotype (SASP) influences the activity of CAR T cells. The proposal aims to elucidate the exact mechanism(s) whereby senescence stimulates CAR T activity: through modulation of microenvironment and/or CAR T activity itself and exploit this knowledge to develop enhanced CAR T constructs of combinatorial approaches to improve CAR T efficacy in solid tumors. Overall these two projects will shed light for the first time into the possibility of combining the fields of senescence and cellular therapy and will lead to the development of highly effective senolytic agents as well as new strategies to improve the efficacy of CAR T cells in solid tumors.

项目摘要/摘要衰老是一个细胞程序，可导致不可逆的细胞周期停滞，响应压力。虽然在短期促进组织稳态的恢复，缺乏衰老细胞的免疫清除率因此，它们的慢性积累导致了慢性促炎环境，已被证明促进肿瘤发育并促进与慢性组织相关的多种病理肺部或肝纤维化，糖尿病和动脉粥样硬化等损害。以前的鼻溶剂方法依赖于使用具有脱靶毒性的非选择性化学抑制剂，并欠对于衰老细胞之间的异质性，效率低下。我的论文项目的长期目标是首次开发嵌合抗原受体（CAR）T细胞作为活鼻溶剂。作为第一步为了开发鼻溶性汽车，我们将确定衰老特异性的表面分子，以更好地识别，表征和靶向衰老细胞。同时，我们将利用这些分子的选择性特征为了产生鼻溶性汽车T细胞，然后我们将其表征它们的功效和安全性。临床前衰老模型。我研究生学习的最初几年的初步数据强烈支持提出的工作的可行性：我们已经主要鉴定出一个细胞表面分子在衰老细胞上表达并开发了针对它的汽车T细胞。我们进一步提供初步数据表明这些汽车T细胞是真正能够消除培养物和在老鼠。在我的其余博士工作中，我们继续验证蛋白质和鼻溶性型汽车T细胞并获得更好地了解他们的行动机制和安全性，并利用我们的发现来发展增强具有新确定的因素的版本以及组合定位策略。拟议的完成工作将导致有效的塞溶性汽车T细胞的发展，并为其临床提供进一步的数据发展是癌症的新型治疗选择，以及许多其他衰老相关疾病。我的博士后研究将继续研究衰老和CAR T细胞，但重点略有变化，以便了解衰老如何相关的分泌表型（SASP）影响汽车T细胞的活性。该提案旨在阐明确切机制衰老刺激CAR T活性：通过调节微环境和/或CAR T活动本身并利用这一知识来开发组合方法的增强型构建体以改进实体瘤的汽车效力。总体而言，这两个项目将首次阐明结合衰老和细胞疗法的领域，将导致高效的发展塞溶剂剂以及提高CAR T细胞在实体瘤中疗效的新策略。