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.

项目概要/摘要衰老是一种细胞程序，会因应激而导致不可逆的细胞周期停滞。虽然在短期内它促进组织稳态的恢复，衰老细胞缺乏免疫清除因此，它们的长期积累会导致慢性促炎症环境，已被证明可以促进肿瘤发展并导致与慢性组织相关的各种病理损害如肺或肝纤维化、糖尿病和动脉粥样硬化等。以前的 senolytic 方法依赖于使用具有脱靶毒性的非选择性化学抑制剂，并且由于衰老细胞之间的异质性，是低效的。我的论文项目的长期目标是首次开发嵌合抗原受体 (CAR) T 细胞作为活的衰老抑制剂。作为第一步为了开发 senolytic CAR T，我们将识别衰老特异性表面分子，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目的是生产 senolytic CAR T 细胞，然后我们在以下方面表征其功效和安全性：临床前衰老模型。我研究生学习最初几年的初步数据强烈支持拟议工作的可行性：我们已经确定了一种主要的细胞表面分子在衰老细胞上表达并开发出针对它的 CAR T 细胞。我们进一步提供初步数据表明这些 CAR T 细胞是真正的衰老细胞，能够消除培养物和环境中的衰老细胞老鼠。在我剩下的博士工作中，我们继续验证蛋白质和 senolytic CAR T 细胞并获得更好地了解其作用机制和安全性，并利用我们的发现来开发增强型版本以及具有新确定因素的组合目标策略。完成拟议的这项工作将导致有效的 senolytic CAR T 细胞的开发，并为其临床提供进一步的数据开发作为癌症以及广泛的其他衰老的新治疗选择相关疾病。我的博士后研究将继续研究衰老和 CAR T 细胞，但稍微改变焦点，以尝试了解衰老相关的分泌表型是如何发生的 (SASP) 影响 CAR T 细胞的活性。该提案旨在阐明确切的机制，从而衰老刺激 CAR T 活性：通过调节微环境和/或 CAR T 活性本身并利用这些知识来开发组合方法的增强型 CAR T 结构，以改善 CAR T 在实体瘤中的疗效。总的来说，这两个项目将首次揭示以下可能性：将衰老和细胞治疗领域相结合，将导致高效治疗的发展抗衰老药物以及提高 CAR T 细胞在实体瘤中疗效的新策略。