Max Jan, MD, PhD

Chronic Lymphocytic Leukemia (CLL) is the most prevalent adult leukemia. There is a pressing need for more effective therapeutic strategies for people with relapsed or refractory CLL. Chimeric antigen receptor (CAR) T cells are immune cell therapies in which a patient’s own T cell are collected, engineered to engage and attack tumor cells, and then returned to the body. While CAR T cell therapies have transformed the care of multiple types of leukemias and lymphomas, progress has been limited for CLL, in large part because CLL cells possess many signals that render T cell dysfunctional. Indeed, people with CLL are often immunosuppressed and are at heightened risk of infections. Here we propose to use synthetic biology approaches to intercept the proteins on CAR T cells that receive these inhibitory signals and route them to our endogenous protein degradation machinery for destruction, thereby overcoming CLL-mediated suppression. The proposed work leverages emerging technologies developed in our lab enabling drug-dependent degradation of inhibitory proteins in CAR T cells, so that these dysfunction-resistant CAR T cells can be tuned and personalized for optimal safety and predictability. Once completed, this study will design, build, and test next-generation cellular immunotherapies with the potential for direct translation to the care of people with CLL and many other forms of leukemia and lymphoma where T cell dysfunction limits patient responses to CAR T cell therapies.