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.

癌症是我们这个时代最严重的人类健康挑战之一，有1810万新病例和950万