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

定义衰老在限制 CAR T 细胞治疗效果中的作用

• 批准号: 10729505
• 负责人: Tara Murty
• 金额: $ 4.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729505
• 关键词: Address; Adoptive Cell Transfers; Age; Antigen Targeting; B lymphoid malignancy; Biology; Blood Component Removal; CAR T cell therapy; Catalytic Domain; Cell Aging; Cell Therapy; Cell physiology; Cells; Cellular biology; Cessation of life; Characteristics; Chemicals; Chemistry; Chronology; Clinical; Computer Analysis; Data; Dedications; Development; Engineering; Fellowship; Functional disorder; Funding; Future; Genetic Engineering; Goals; Health; Human; Immunology; Immunotherapy; Incidence; Infusion procedures; Interdisciplinary Study; Length; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Medical; Medicine; Mentorship; Molecular; Multienzyme Complexes; Oncology; Outcome; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Population; Proliferating; Recording of previous events; Research; Resources; Role; Scientist; Solid Neoplasm; Surface; T-Lymphocyte; Telomerase; Telomerase inhibition; Testing; Therapeutic; Time; Training; Training Programs; Treatment Efficacy; Tumor Burden; Universities; Work; beta-Galactosidase; cancer therapy; career; chimeric antigen receptor; chimeric antigen receptor T cells; clinical predictors; disorder control; epigenome; exhaustion; experience; innovation; insight; loss of function; medical schools; next generation; novel; predictive marker; programs; response; senescence; telomere; therapy design; tool; transcriptome; treatment response

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.

癌症是我们时代最深刻的人类健康挑战之一，有1,810万例新病例和9.5例 2018年全球与癌症相关的数百万次死亡，预计到2040.1年将增加60％以上 嵌合抗原受体（CAR）T细胞疗法已通过设计靶向彻底改变了肿瘤学 以前无法治疗的癌症的抗原。但是，在CAR T细胞疗法经验上只有不到一半的患者 长期疾病控制和CAR T细胞尚未介导实体瘤的持续反应。2T细胞 精疲力尽已广泛特征并与CAR T细胞功能障碍相关，但衰老的作用 3衰老的T细胞已显示出有缺陷的杀戮能力，并且 4此外，端粒酶的水平已被证明可以控制 人类T细胞的寿命，水平增加延迟衰老。5 我对该项目的中心假设是，T细胞衰老限制了收养细胞疗法的功效，I 可以描述端粒酶在T细胞中的端粒依赖性和非依赖性作用，并确定衰老 预测汽车治疗反应的标志物，与患者特征相关。在提议中 工作，我将：（i）定义汽车T细胞中的衰老特征，并与疲惫和功能相关，（ii）使用 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） 将T细胞衰变特征与临床措施相关联的T细胞衰变特征和CAR T输注产物。共同 拟议的工作将调查汽车衰老作为一种分层和预测性临床相关性，提供 机械洞察力告知越来越有效的汽车癌症治疗。 奖学金培训将在斯坦福大学医学院进行，并由主要研究和 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 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），我受到支持将免疫学，化学生物学和计算 推进癌症治疗的汽车疗法的策略。 Crystal Mackall博士是理想的赞助商 由于她在T细胞生物学和翻译细胞疗法方面的专业知识，该提案，她的联邦资助计划 在发展和表征免疫疗法以及她对医师科学家职业的奉献 指导。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Sean Bendall博士带来了单细胞，高含量计算分析的专业知识。