Understanding and manipulating programmed cell death (PCD) pathways to facilitate lymphoid tumor killing by CAR T cells

了解和操纵程序性细胞死亡 (PCD) 途径以促进 CAR T 细胞杀死淋巴肿瘤

基本信息

批准号：
10540403
负责人：
Marcela Valderrama Maus
金额：
$ 68.91万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-07 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540403
关键词：
Affect Alleles Antibodies Antigen Targeting Antigens Apoptosis Apoptotic Attention BCL1 Oncogene Biological Assay CAR T cell therapy CD19 Antigens CD19 gene CD8B1 gene Cell Death Cell Death Induction Cell Death Signaling Process Cell-Mediated Cytolysis Cells Cessation of life Data Drug Combinations Drug resistance Engineering Epidermal Growth Factor Receptor Genes Genetic Genetic Engineering Genomic approach Glioblastoma Goals Granzyme Hematopoietic Neoplasms Immune system Immunology Immunotherapy In Vitro Laboratories Lead Life Liquid substance Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Mediating Mitochondria Multiple Myeloma Mus Mutation Pathway interactions Patients Pharmaceutical Preparations Pharmacogenetics Plasma Cells Predisposition Proteins Receptor Signaling Resistance Signal Transduction Solid Solid Neoplasm Surface T-Lymphocyte Techniques Testing Tumor Biology Tumor Cell Line Xenograft Model Xenograft procedure cancer cell cancer type cell killing chimeric antigen receptor T cells cytotoxicity density drug candidate effector T cell engineered T cells functional genomics gain of function genetic approach in vivo inhibitor innovation invention knockout gene loss of function lymphoid neoplasm mouse model mutant neoplastic cell perforin pharmacologic resistance mechanism response small molecule standard care tool tumor

项目摘要

PROJECT SUMMARY Recent advances using CAR T cells in lymphoid malignancies have made it clear that manipulation of the host immune system can radically alter the course of a cancer. Although there have been lifesaving responses in some patients, all too many patients have inadequate responses. Some patients and tumor types have been more amenable to CAR T cell therapies than others, despite similar levels of antigen expression, uniformity, and density. The exact mechanisms by which CAR T cells induce tumor cell death are unknown, and may be due to a combination of multiple T cell effector functions that ultimately result in cell death, potentially by triggering programmed cell death in tumor cells. Our overall hypothesis is that CAR T cells mediate tumor cell death by inducing programmed cell death (PCD) pathways in target cells. A logical corollary of this hypothesis is that one potential mechanism of resistance, which has received scant attention, is genetic or functional resistance to PCD in the target tumor cells. Furthermore, we hypothesize that the state of PCD constituents in tumor cells confers sensitivity or resistance to T-cell mediated killing, and that this relative resistance can be overcome with drugs that enhance PCD signaling in tumor cells. Finally, because systemically administered drugs that enhance PCD signaling may also affect CAR T cells, we propose genetic engineering approaches to render CAR T cells resistant to candidate PCD-enhancing drugs. This is a collaborative project between an expert in CAR T cells and immunology and an expert in programmed cell pathways and tumor biology. Together we aim to define the effector functions of T cells that induce tumor cell death (Aim 1), define the programmed cell death pathways in tumors that confer sensitivity or resistance to CAR T cell mediated killing (Aim 2), and use innovative strategies to enhance CAR T cell killing of tumor cells by manipulating PCD pathways using small molecule drugs in combination with genetic engineering of the CAR T cells.

项目概要在淋巴恶性肿瘤中使用 CAR T 细胞的最新进展表明，对宿主的操纵免疫系统可以从根本上改变癌症的进程。尽管已经采取了挽救生命的应对措施一些患者，太多的患者反应不足。一些患者和肿瘤类型已被尽管抗原表达水平、均匀性、和密度。 CAR T 细胞诱导肿瘤细胞死亡的确切机制尚不清楚，可能是由于多种 T 细胞效应功能的组合最终导致细胞死亡，可能是通过触发肿瘤细胞的程序性细胞死亡。我们的总体假设是 CAR T 细胞介导肿瘤细胞通过诱导靶细胞中的程序性细胞死亡（PCD）途径而死亡。该假设的逻辑推论一种潜在的耐药机制是遗传性或功能性的，但很少受到关注。靶肿瘤细胞对 PCD 的抵抗力。此外，我们假设 PCD 成分的状态肿瘤细胞对 T 细胞介导的杀伤具有敏感性或抵抗力，并且这种相对抵抗力可以是通过增强肿瘤细胞中 PCD 信号传导的药物来克服这一问题。最后，由于系统性管理增强PCD信号传导的药物也可能影响CAR T细胞，我们提出基因工程方法使 CAR T 细胞对候选 PCD 增强药物产生耐药性。这是一个合作项目 CAR T 细胞和免疫学专家，程序细胞途径和肿瘤生物学专家。我们共同的目标是定义诱导肿瘤细胞死亡的 T 细胞的效应功能（目标 1），定义肿瘤中的程序性细胞死亡途径赋予对 CAR T 细胞介导的杀伤敏感性或抗性（目标2），并使用创新策略通过操纵PCD来增强CAR T细胞对肿瘤细胞的杀伤使用小分子药物与 CAR T 细胞基因工程相结合的途径。