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

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.