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

癌症是我们这个时代最深刻的人类健康挑战之一，有1810万新病例和950万新病例。 2018年全球癌症相关死亡人数为100万，预计到2040年将增加60%以上。 嵌合抗原受体（CAR）T细胞疗法通过工程化靶向治疗肿瘤， 以前无法治疗的癌症的抗原。然而，不到一半的CAR T细胞治疗患者 长期疾病控制，并且CAR T细胞在实体瘤中没有介导持续的应答。 疲惫已被广泛表征并与CAR T细胞功能障碍有关，但衰老的作用 衰老的T细胞已被证明表现出有缺陷的杀伤能力， 4此外，端粒酶的水平已被证明可以控制肿瘤细胞的生长。 人类T细胞的寿命，随着水平的增加而延缓衰老。 我对这个项目的中心假设是，T细胞衰老限制了过继细胞治疗的疗效， 可以描绘T细胞中端粒酶的端粒依赖性和非依赖性作用， 预测CAR T治疗反应并与患者特征相关的标志物。拟议 工作，我将：（i）定义CAR T细胞中的衰老特征，并与衰竭和功能相关，（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，和（iii） 将单采血液成分术和CAR T输注产品中的T细胞衰老特征与临床测量相关联。总的来说， 拟议的工作将研究CAR T衰老作为分层和预测临床相关性， 机械见解为越来越有效的CAR T癌症治疗提供信息。 奖学金培训将在斯坦福大学医学院进行， 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 医学科学家培训计划（MSTP），斯坦福大学化学，工程和人类健康医学 （ChEM-H）化学-生物学界面（CBI）培训计划和斯坦福大学跨学科研究生 奖学金（SIGF），我支持独特的整合免疫学，化学生物学，和计算 推进CAR T疗法治疗癌症的策略。Crystal Mackall博士是 这一提议是由于她在T细胞生物学和转化细胞疗法方面的专业知识，她的联邦资助计划， 在开发和表征免疫疗法，以及她的奉献精神，医生科学家的职业生涯 导师制合作者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， 合作者Sean Bendall博士带来了单细胞，高内容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.