Defining the Role of Senescence in Limiting Therapeutic Efficacy of CAR T Cells

癌症是我们这个时代人类健康面临的最严峻挑战之一，有1810万新病例和950万人 2018年全球与癌症相关的死亡人数达到100万人，预计到2040.1年，每个人的死亡人数都将增加60%以上 嵌合抗原受体(CAR)T细胞疗法通过工程化靶向 以前无法治愈的癌症上的抗原。然而，接受CAR T细胞治疗的患者中，只有不到一半的人经历过 长期疾病控制，CAR T细胞在实体瘤中没有介导持续反应。 精疲力竭已被广泛描述并与CAR T细胞功能障碍有关，但衰老的作用 3衰老的T细胞已被证明具有缺陷的杀伤能力和 负调控功能的发展。4此外，端粒酶水平已被证明控制着 人类T细胞的寿命，水平的增加可以延缓衰老。 我对这个项目的中心假设是T细胞衰老限制了过继细胞疗法的疗效，而我 可以描述T细胞中端粒依赖和不依赖的端粒酶的作用，并识别衰老 标记物预测CAR T治疗反应，并与患者特征相关。在建议的 在工作中，我将：(I)定义CAR T细胞的衰老特征，并与疲惫和功能相关，(Ii)利用 基因工程，以询问端粒酶活性对T细胞功能和表型的影响，以及(Iii) 采集器和CAR-T输液产品中T细胞衰老特征与临床措施的关系总而言之， 拟议的工作将调查CAR T衰老作为一种分层和预测性的临床相关性，提供 为日益有效的CAR T癌症治疗提供信息的机械性见解。 奖学金培训将在斯坦福大学医学院进行，拥有一流的研究和 强调跨学科研究和创新的临床资源。作为斯坦福大学的研究生 斯坦福大学人类健康化学、工程和医学医学科学家培训计划(MSTP) (化学-H)化学-生物界面(CBI)培训计划和斯坦福大学跨学科毕业生 奖学金(SIGF)，我被支持将免疫学、化学生物学和计算 推进癌症治疗的CAR T疗法的策略。克里斯托·麦考尔博士是 由于她在T细胞生物学和翻译细胞疗法方面的专业知识，她的联邦资助项目 在开发和表征免疫疗法方面，以及她对医生-科学家职业生涯的奉献 师徒关系。合作者Steven Artandi博士带来了细胞衰老和端粒酶动力学方面的专业知识，以及 合作者肖恩·本德尔博士带来了单细胞、高含量计算分析方面的专业知识。

Cancer is one of the most profound human health challenges of our time, with 18.1 million new cases and 9.5 million cancer-related deaths worldwide in 2018, each predicted to increase by more than 60% by the year 2040.1 Chimeric antigen receptor (CAR) T cell therapy has revolutionized oncology through engineered targeting of antigens on previously untreatable cancers. However, less than half of patients on CAR T cell therapy experience long-term disease control, and CAR T cells have not mediated sustained responses in solid tumors.2 T cell exhaustion has been extensively characterized and linked to CAR T cell dysfunction, but the role of senescence is still poorly understood.3 Senescent T cells have been shown to manifest defective killing abilities and the development of negative regulatory functions.4 Moreover, levels of telomerase have been shown to control the lifespan of human T cells, with increased levels delaying senescence.5 My central hypothesis for this project is that T cell senescence limits the efficacy of adoptive cell therapy, and I can delineate telomere-dependent and -independent roles of telomerase in T cells and identify senescent markers predictive of CAR T treatment response and correlated with patient characteristics. In the proposed work, I will: (i) define senescent features in CAR T cells and correlate with exhaustion and functionality, (ii) utilize genetic engineering to interrogate the impact of telomerase activity on T cell function and phenotype, and (iii) correlate T cell senescent features in apheresis and CAR T infusion product with clinical measures. Collectively, the proposed work will investigate CAR T senescence as a stratifying and predictive clinical correlate, providing mechanistic insights informing increasingly effective CAR T cancer treatments. The fellowship training will take place at the Stanford University School of Medicine, with premier research and clinical resources that emphasize interdisciplinary research and innovation. As a graduate fellow in the Stanford Medical Scientist Training Program (MSTP), Stanford Chemistry, Engineering, and Medicine for Human Health (ChEM-H) Chemical-Biology Interface (CBI) training program, and Stanford Interdisciplinary Graduate Fellowship (SIGF), I am supported to uniquely integrate immunology, chemical biology, and computational strategies to advance CAR T therapies for the treatment of cancer. Dr. Crystal Mackall is the ideal sponsor for this proposal due to her expertise in T cell biology and translational cell therapies, her federally funded programs in developing and characterizing immunotherapies, as well as her dedication to physician-scientist career mentorship. Collaborator Dr. Steven Artandi brings expertise in cell senescence and telomerase dynamics, and collaborator Dr. Sean Bendall brings expertise in single-cell, high-content computational analyses.