The promise of clinically active CAR T cells for solid tumors continues to be limited by the immunosuppressive tumor micro-environment (TME). Here we engineer CAR T cells with synthetic cytokine circuits in which a tumor-specific synthetic Notch (synNotch) receptor drives IL-2 production. This cell autonomous mechanism for IL-2 production dramatically improves T cell infiltration into multiple challenging immune-excluded syngeneic tumor models leading to complete tumor clearance without systemic toxicity.

Tumors suppress T cell activity by both inhibiting T cell receptor (TCR) signaling and consuming inflammatory cytokines like IL-2. Within these constraints we found that the exact circuit architecture used to produce IL-2 is critical to the activity of these synthetic cytokine circuits. By bypassing requirements for T cell activation and by providing IL-2 in a preferred autocrine configuration these local IL-2 induction circuits overcome the main modes of tumor immune suppression and provide a potential general solution for driving effective T cell activity against immune-suppressed solid tumors.

Presenter Biography:
Dr. Greg Allen is an Assistant Professor of Medicine at the University of California San Francisco and a fellow at the UCSF Cell Design Institute. He received his MD and PhD at Stanford University and clinical training at The Johns Hopkins Hospital and the University of California San Francisco. He then completed his post-doctoral studies in the laboratory of Prof Wendell Lim as a Jane Coffin Childs fellow. His research is focused on developing next-generation engineered immune cell therapies to advance the treatment of solid tumors. In his work, he has helped pioneer the development of combinatorial antigen-gated CAR T cells and tools for cell-autonomous cytokine delivery.

Author