Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for haematological malignancies, with six products receiving FDA approval between 2017 and 2022. The University of Pennsylvania's Center for Cellular Immunotherapies, co-founded by Dr. Carl June and Dr. Bruce Levine, played a foundational role in translating CD19-targeting CAR-T therapy into clinical practice, while European centres including Institut Gustave Roussy have been integral to Phase III validation and post-marketing studies. This review comprehensively examines the structural evolution of CAR constructs from first to fourth generation, the immunological mechanisms underpinning tumour killing and therapy-associated toxicities, and the clinical performance of approved CAR-T products. We address key limitations including manufacturing complexity, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), T cell exhaustion, and antigen loss, and review emerging strategies including armoured CAR-T cells, logic-gated CAR designs, CRISPR-engineered allogeneic CAR-T cells, and CAR-NK platforms. The expanding application of CAR-T technology to solid tumours and autoimmune diseases is also reviewed.
