The quintessential role for CAR T cell therapy in children, adolescents and young adults with cancer.

Early successes achieved with the CD19-targeted chimeric antigen receptor (CAR) T cell product tisagenlecleucel for the treatment of paediatric B cell acute lymphoblastic leukaemia (B-ALL) led to a historic first FDA approval of a gene therapy. Widespread CAR T cell commercialization followed, along with expansion to other indications and earlier disease settings owing to clear survival benefits. However, commercial development of additional cell therapies for paediatric malignancies has stagnated, despite several products being brought to market as treatments for various haematological malignancies in adults. In contrast to the consistent efficacy achieved across B cell malignancies, CAR T cell approaches have yet to demonstrate durable activity in patients with acute myeloid leukaemia (AML), T cell acute lymphoblastic leukaemia, solid tumours and/or central nervous system cancers, with both biological factors and broader issues of development and access constraining the field. Herein, we showcase the foundational leaps achieved through the initial trials and commercialization of CAR T cell products and contextualize how these early experiences have moulded the field. We review currently approved and investigational CAR T cell therapies for paediatric and young-adult patients, including key considerations regarding safety, access and future directions. We also discuss additional immunotherapy options that guide clinical decision-making regarding optimal utilization of CAR T cells. Although clearly tolerable and efficacious, the CD19-targeted CAR T cell strategy requires ongoing refinement, and research efforts are now geared towards fully exploiting CAR T cells and other immunotherapies to improve survival with broadened access across disease states. This Review outlines the fundamental role of chimeric antigen receptor (CAR) T cell therapy for children, adolescents and young adults (CAYAs) with relapsed and/or refractory B cell acute lymphoblastic leukaemia, emphasizing the crucial need to further exploit CAR T cells and other immunotherapies to improve survival with broadened access across disease states. Opportunities and challenges for expanding CAR T cell therapy to other haematological and non-haematological malignancies in CAYAs are also discussed.