STRATEGIES TO ADDRESS TUMOR INTRINSIC MECHANISMS OF RESISTANCE TO ADOPTIVE CHIMERIC ANTIGEN RECEPTOR THERAPY

Chimeric antigen receptors (CAR) are synthetic receptors that combine the single chain variable fragment (scFv) of a monoclonal antibody with the ζ-chain and costimulatory domains from the T cell receptor complex. Gene transfer of CARs into T cells redirects T cell antigen specificity through the scFv and promotes T cell activation and proliferation through costimulatory signals. The infusion of CAR-T cells in patients with B cell malignancies has led to durable complete remission. However, there is still considerable work to be done to improve the efficacy of CAR-T cell therapy. In this dissertation we propose two strategies to address resistance to adoptive CAR-T cell therapy. In Chapter 1, we begin by summarizing the progress made in the field of adoptive T cell therapies and the drawbacks of the achievements that led to the development of CAR-T cell therapies. We then detail the evolution of CAR-T cell therapies and review the advances being made to improve the efficacy of CAR-T cells in the treatment of solid tumor malignancies. Chapter 1 ends with an account of the challenges still facing CAR-T cell therapy: tumor escape and tumor heterogeneity. Tumor escape resulting from selective pressure by CAR-T cells is becoming an increasingly common cause of resistance to CAR-T cell therapy. The field has addressed the need for multi-redirect CAR-T cells but with suboptimal strategies that significantly increase the cost or compromise the efficacy of adoptive CAR-T cells. Chapter 2 proposes a novel strategy to prevent relapse occurring from tumor escape by simultaneously targeting multiple tumor-associated antigens using single domain antibody mimics. In Chapter 3 we undertake the intrinsic tumor heterogeneity that is a root cause of resistance to adoptive CAR-T cell therapy. We identify B7-H3 as a tumor-associated antigen that is universally expressed in malignancies across organs and tissues of diverse origin and demonstrate that a novel CAR targeting B7-H3 possesses robust anti-tumor activity and positive safety profile. In Chapter 4, we conclude with a discussion of how the proposed therapies provided a foundation upon which to refine and improve the efficacy of adoptive CAR-T cell therapy.Doctor of Philosoph