Joseph J. Muldoon, PhD, Postdoctoral Fellow University of California, San Francisco Area of Research: All Cancers The engineering of immune cells with programmable functions is a rapidly advancing therapeutic modality. Receptors such as chimeric antigen receptors (CARs) can be made to marshal T cell responses against tumors bearing specified antigens. However, two major challenges facing these synthetic receptors are that (a) they can be relatively limited in sensitivity, allowing cancer cells to evade detection and relapse as refractory to treatment, and (b) there is a risk of killing non-tumor cells that also express the target antigen, leading to severe toxicities. For these reasons, strategies are needed to improve the efficacy and safety of these treatments. Dr. Muldoon’s research aims to develop high-throughput screening methods and fundamental design principles for implementing next-generation receptors that may be used as alternatives to CARs. Specifically, he will investigate new architectures that exhibit CAR-like programmability and that can benefit from endogenous T cell receptor (TCR)-like sensitivity and regulation. These receptors will be introduced into primary human T cells via precise genome editing and evaluated in large-scale pooled format in vivo to identify the most effective variants. By mapping their functionality to their individual characteristics, he will seek to derive a set of rules for extending these receptors to target other antigens in the future. Multi-input circuits will also be developed to impart logic-gated specificity to the now-sensitive T cell activation. These advances may be able to help overcome persistent challenges in cell-based immunotherapy. Projects and Grants Design of synthetic receptors for sensitive and specific antigen targeting University of California, San Francisco | All Cancers | 2021 | Justin Eyquem, PhD
