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

项目总结 利用CAR T细胞治疗淋巴系统恶性肿瘤的最新进展表明，对宿主的操纵 免疫系统可以从根本上改变癌症的进程。尽管已经有了一些拯救生命的反应 有些病人，太多的病人反应不充分。一些患者和肿瘤类型已经被 更容易接受CAR T细胞疗法，尽管抗原表达水平相似，一致性， 和密度。CAR T细胞诱导肿瘤细胞死亡的确切机制尚不清楚，而且可能是 由于多种T细胞效应器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死亡。我们的总体假设是CAR T细胞介导肿瘤细胞 通过在靶细胞中诱导程序性细胞死亡(PCD)途径而死亡。这一假设的逻辑推论 一种潜在的抗药性机制是遗传的或功能性的，但很少被关注 靶肿瘤细胞对PCD的耐药性。此外，我们假设PCD成分的状态在 肿瘤细胞对T细胞介导的杀伤具有敏感性或抵抗力，这种相对抵抗力可以是 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信号的药物也可能影响CAR T细胞，我们提出了基因工程方法来 使CAR T细胞对候选的PCD增强药物产生抗药性。这是一个合作项目，由 CAR T细胞和免疫学专家，程序化细胞通路和肿瘤生物学专家。 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 肿瘤中对CAR T细胞介导的杀伤敏感或抵抗的程序性细胞死亡途径 (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。

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.