Enhancing CAR T cell safety with new universal CAR systems and anatomically restricted tumor targeting

Abstract

Chimeric antigen receptor (CAR) T cells are a potent class of immunotherapy that have revolutionized the treatment of hematological malignancies. However, high relapse rates and severe side effects have limited their impact. As the field progresses and CAR T cells are used to target more complex and diverse cancer populations, innovative solutions are needed to safely and controllably improve tumor targeting and prevent relapse. Universal CARs are one such innovation, as they enable highly controllable, multivalent tumor targeting via bifunctional intermediate adaptor molecules. Here, we discuss the state of research on universal CARs and explore some of the current approaches to enhance their specificity (Chapter 1). We then describe our own contributions to the field through the development of a new universal CAR specific for conjugated derivatives of biotin (Chapter 2) and a novel IF-THEN gating system to spatially restrict CAR T cell activity to tumor microenvironments using polymeric biomaterials (Chapter 3). At the end of each chapter, we discuss current limitations and future directions of this work.