Response and resistance to chimeric antigen receptor T cell therapy in human solid tumors using spatial multi-omics

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The development of next-generation chimeric antigen receptor (CAR) T cell therapy for solid tumors requires a comprehensive understanding of how host and tumor characteristics impact response. Tumor microenvironment (TME) barriers to CAR T cell trafficking and cytotoxic function are myriad, including recruitment of suppressive immune cells, antigen heterogeneity, and T cell-intrinsic dysfunction. Here, we use spatial multi-omic analysis of longitudinal biopsies from patients with metastatic castration-resistant prostate cancer treated with CAR T cells to define mechanisms with greater detail than previously possible. We multiplex co-detection by indexing (CODEX), GeoMx, and CosMx assays to evaluate immune features at the single cell, cell niche, and tissue levels and then determine associations with CAR T cell infiltration and clinicopathologic factors. Our preliminary and ongoing analyses indicate that the TME is profoundly impacted by CAR T-cell therapy in both spatiotemporal form and functional state, with hallmark changes in tumor programs, myeloid cell polarization, suppressive pathways, and elicitation of inflammatory mediators that correlate with toxicity and response. The goal of these studies is to use opportunities in spatial multi-omics to define new biology of CAR T cells in humans and catalyze reverse translational studies for future CAR T cell therapy.


Andrew J. Rech, MD, Ph.D.
Post-Doctoral Research Fellow
University of Pennsylvania, Philadelphia