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Abstract
Chimeric antigen receptor (CAR) T-cell therapies have transformed the therapeutic landscape for hematological malignancies by providing patients with relapsed or refractory disease a late-line option. While many patients can achieve long-term remission, the clinical efficacy of CAR T cells has been limited by high rates of non-response and early relapse. Thus, new strategies to improve existing CAR T-cell products and develop novel CAR T-cell therapies are necessary. In this dissertation, I leverage multimodal sequencing analysis of patient-derived CAR T cells to investigate three central questions in the field: 1) How do CAR T cells differentiate following infusion? 2) What immunological factors enable successful salvage CAR T-cell therapy? 3) Can durable patient responses be predicted based on early CAR T-cell signatures? In Chapter 1, I provide an overview of CAR T-cell therapy and current discoveries of in vivo CAR T-cell differentiation and functionality enabled by single-cell sequencing. In Chapter 2, I describe how post-infusion CD19 CAR T cells follow a two-stage differentiation model governed by distinct phenotypic and clonotypic profiles. In Chapter 3, I report that a T resident memory-like BCMA CAR T-cell phenotype plays an important role in enabling successful salvage therapy after failed BCMA CAR T-cell therapy. In Chapter 4, I provide an in-depth characterization of the early drivers of CAR T-cell stemness that distinguish durable versus nondurable response in patients receiving BCMA CAR T-cell therapy. Altogether, these findings provide a mechanistic foundation that enable the development of next-generation CAR T-cell therapies.