CAR-T Cell Therapy in Haematologic Malignancies

Chimeric Antigen Receptor T-cell (CAR-T) therapy has emerged as a revolutionary modality in cancer immunotherapy, particularly transforming the prognosis of relapsed/refractory haematologic malignancies. This chapter offers a comprehensive overview of CAR-T cell therapy, tracing its evolution, mechanistic underpinnings, and current clinical applications. It begins by detailing the structural domains of a CAR construct and categorizing its development into five generations, alongside newer variants like universal CARs, TanCARs, and inhibitory CARs aimed at enhancing precision and safety. The historical timeline outlines major milestones in adoptive cell therapy, culminating in current FDA-approved CAR-T products for B-cell malignancies and multiple myeloma. Key challenges such as tumour escape via antigen loss, immune exhaustion, and bone marrow microenvironment resistance are discussed, highlighting the need for strategic combinatorial approaches. Manufacturing techniques—both ex vivo and in vivo—are described, along with regulatory considerations. Clinical indications and FDA-approved products are tabulated with their trial data. The chapter further addresses unique CAR-T-related complications, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections, hypogammaglobulinemia, cytopenias, and secondary hemophagocytic lymphohistiocytosis (sHLH), along with evidence-based management protocols. Monitoring strategies for CAR-T persistence, immune reconstitution, and minimal residual disease (MRD) are outlined, emphasizing their prognostic and therapeutic implications. Finally, the chapter explores long-term follow-up frameworks modelled on allogeneic transplant clinics, detailing common late effects and the importance of multidisciplinary care. As CAR-T therapy expands to solid tumours and autoimmune diseases, this chapter underscores the pivotal role of innovation in design, post-infusion strategies, and real-world data integration to ensure sustained efficacy and safety.