Duvelisib Promotes Mitochondrial Fusion and Epigenetic Reprogramming to Drive Therapeutic T Cell Persistence and Function

Chronic lymphocytic leukemia (CLL), a cancer of B-lymphocytes, is the most common leukemia in adults. While current frontline therapies for CLL, such as ibrutinib or combination venetoclax and obintuzumab, have significantly improved clinical outcome for patients with treatment naïve CLL and relapsed and refractory CLL (RR-CLL), complete response (CR) rates for RR-CLL patients on ibrutinib remain between 5-14% and 42% for patients on venetoclax and obintuzumab (1, 2). With the advent of chimeric antigen receptor T cells (CART), CR for RR-CLL have increased to around 26-29%, yet this is in sharp contrast to the 70-93% CR achieved in acute lymphocytic leukemia (2). This discrepancy in response is in part due to the inherently immunosuppressive nature of CLL, such that CLL patients are significantly deficient in CD8 co-receptor expressing (CD8+) T cells, including stem cell-like memory T (Tscm) and central memory T (Tcm) cells (2). As the prevalence of Tscm and Tcm cell populations is directly correlated to the in vivo persistence and efficacy of CART, elucidating translatable mechanisms to selectively expand Tscm and Tcm from CLL patients is key to improving the efficacy CART cell therapy for CLL patients.