Description of Research Expertise

A major factor limiting the efficacy of chimeric antigen receptor (CAR) T cell therapy is T cell exhaustion, wherein chronic CAR signaling via antigen-independent CAR aggregation or high tumor burden drives global transcriptional and epigenetic alterations, overexpression of immune inhibitory receptors (ex. PD-1), and diminished anti-tumor function. My postdoctoral research demonstrated that transient cessation of CAR signaling, or “rest”, in exhausted CAR-T cells via enforced oscillations in CAR surface expression or pharmacologic inhibition of CAR signaling (Weber et al., Blood Adv, 2019) restores anti-tumor functionality through epigenetic remodeling (Weber et al., Science, 2021). This work is foundational to my independent research program centered around endowing human CAR-T cells with exhaustion resistance and improved durability. Utilizing an array of pharmacologic, gene-editing, and bioengineering approaches, my lab will identify and modulate transcriptional and epigenetic pathways that redirect human T cells towards more therapeutic cell states. Multi-omics analyses on experimental and patient CAR-T cells will enable us to link epigenetic features (ex. global or site-specific histone modifications) to cell phenotype, function, and patient outcomes, thereby informing our T cell engineering efforts. Collectively, our work will uncover molecular programs that drive human CAR-T cell dysfunction, identify targets for therapeutic intervention, and inform universal strategies that improve CAR-T cell efficacy in cancer patients.