Rescue T cell aging to improve CAR T cell production for elderly cancer patients

Summary T cells play a prominent role in the immunity against malignancies. However, T cell immunity declines with aging. Immunosenescence of T cells leads to terminal differentiation and impaired expansion after stimulation. The age-driven decline in T cell immunity compromises immune control over tumor cells. Many types of cancers such as chronic lymphocytic leukemia (CLL) occur much more frequently in the elderly. T cells in CLL patients show signs of accelerated aging, including reduced proliferative capacity, terminal differentiation, and exhaustion. Most CAR T cells are generated from autologous T cells from cancer patients. As a result of aging and exhaustion of T cells, manufacture and expansion of chimeric antigen receptor (CAR) T cells are more likely to fail in CLL patients. Thus, understanding the molecular mechanism of T dysfunction in natural aging and cancer is critical for boosting immunity and improving cancer treatment in the elderly. Metabolism plays a critical role in regulating T cell proliferation, differentiation and function. We found that aging dysregulates metabolism in CD8 T cells both before and after activation. In addition, our preliminary data showed that rebalancing TCR and cytokine signaling rescued the age-associated defect in expansion of CD8 T cells. However, how natural aging and CLL compromise metabolic adaptation in T cells upon TCR and cytokine signaling is unclear. Strategies to correct defective activation and metabolic adaptation associated with T cell aging remain elusive. Here, we hypothesize that metabolic adaptation to T cell activation is impaired by aging and CLL and can be corrected by rebalancing cytokine and TCR stimulation. We will use cutting-edge metabolism assay to determine the effect of natural aging and CLL on the metabolism of CD8 T cells after TCR and cytokine stimulation. We will also evaluate strategies to improve the generation, expansion, and antitumor immunity of CAR T cells generated from the elderly and CLL patients.