Tuoqi Wu, PhD, CLIP Investigator The University of Texas MD Anderson Cancer Center CAR T cells rarely induce durable remission in solid tumors. Poor persistence and exhaustion of CAR T cells limit their antitumor immunity. Dr. Wu and others characterized a novel stem-like T cell subset that resists exhaustion, persists via self-renewal, and responds potently to checkpoint inhibitors. Notably, stem-like CAR T cells are associated with favorable clinical outcome in cancer patients. Here, Dr. Wu will harness the molecular program of stem-like T cells to improve the efficacy of CAR T cells against solid tumors. He will address several key knowledge gaps and challenges, including paucity of existing stem-like T cells for CAR T cell manufacture, limited tumor infiltration by stem-like CAR T cells, and poorly defined intra-tumoral niche of stem-like CAR T cells. First Dr. Wu will program CAR T cells into stem-like T cells by introducing transcription factors that promote T cell stemness. He will evaluate the synergy between programmed stem-like CAR T cells and PD1 blockade and the effectiveness of the combination therapy in inducing endogenous antitumor T cell response via epitope spreading. Next he will evaluate whether normalizing tumor vasculature enhances tumor infiltration of stem-like CAR T cells. He will use single-cell RNA-Seq and spatial transcriptomics to define the intra-tumoral niche of stem-like CAR T cells and identify receptor-ligand interactions between tumor microenvironment and stem-like CAR T cells. Dr. Wu’s project will produce novel strategies to generate CAR T cells with greater efficacy against solid tumors and provide novel drug development targets. Projects and Grants Harnessing the molecular program of stem-like T cells for CAR T-cell therapy against solid tumors The University of Texas Southwestern Medical Center | All Cancers | 2022
