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

项目摘要 在淋巴恶性肿瘤中使用CAR T细胞的最新进展已经清楚地表明，操纵宿主 免疫系统可以从根本上改变癌症的进程。尽管在过去的几年里， 有些病人，太多的病人没有充分的反应。一些患者和肿瘤类型已经 比其他细胞更适合CAR-T细胞疗法，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是未知的，并且可能是未知的。 由于多种T细胞效应子功能的组合最终导致细胞死亡， 引发肿瘤细胞的程序性细胞死亡。我们的总体假设是CAR T细胞介导肿瘤细胞增殖， 通过诱导靶细胞中的程序性细胞死亡（PCD）途径死亡。这一假设的逻辑推论 一个潜在的耐药机制是遗传性的或功能性的，但很少受到关注 对靶肿瘤细胞中PCD的抗性。此外，我们假设，PCD成分的状态， 肿瘤细胞赋予对T细胞介导的杀伤的敏感性或抗性，并且这种相对抗性可以是 用增强肿瘤细胞中PCD信号的药物来克服。最后，因为系统管理 增强PCD信号传导的药物也可能影响CAR T细胞，我们提出了基因工程方法， 使CAR T细胞对候选PCD增强药物具有抗性。这是一个合作项目， 他是CAR T细胞和免疫学方面的专家，也是程序化细胞通路和肿瘤生物学方面的专家。 我们的目标是共同定义T细胞诱导肿瘤细胞死亡的效应子功能（目标1）， 肿瘤中的程序性细胞死亡途径赋予对CAR T细胞介导的杀伤的敏感性或抗性 (Aim 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细胞的基因工程相结合的途径。

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.