Abstract
Chimeric antigen receptor (CAR) T cell immunotherapy is promising for treatment of blood cancers; however, clinical benefits remain unpredictable, necessitating development of optimal CAR T cell products. Unfortunately, current preclinical evaluation platforms are inadequate owing to their limited physiological relevance to humans. Here we engineer an organotypic immunocompetent chip that recapitulates microarchitectural and pathophysiological characteristics of human leukaemia bone marrow stromal and immune niches for CAR T cell therapy modelling. This leukaemia chip empowers real-time spatiotemporal monitoring of CAR T cell functionality, including T cell extravasation, recognition of leukaemia, immune activation, cytotoxicity and killing. We use our chip to model clinically observed heterogeneous responses such as remission, resistance and relapse under CAR T cell therapy and map factors that drive therapeutic success or failure. Finally, we demarcate functional performance of CAR T cells produced from different healthy donors and patients with cancer, with various CAR designs and protocols, systematically and multidimensionally. Together, our chip introduces an enabling '(pre-)clinical-trial-on-chip' tool for CAR T cell development, which may translate to personalized therapies and improved clinical decision-making.