Abstract

Autologous chimeric antigen receptor (CAR) T-cell therapy has transformed the management of B-cell leukaemia and lymphoma. However, current manufacturing processes present logistical hurdles, restricting broader application. As clinical outcomes can be heavily influenced by the quality of autologous starting materials and production processes, strategies to improve product phenotype are crucial. Short manufacturing processes have the advantage of bringing products to patients more quickly and, in parallel, avoiding the highly differentiated and exhausted CAR T-cell phenotypes associated with prolonged ex vivo manufacture. This Review examines advances in our understanding of what constitutes an effective CAR T-cell product and approaches to improve product quality. Historically, strategies have relied on adjustments in medium composition and selection of less differentiated cell subtypes. Since 2020, the field has been shifting towards reduced-expansion protocols, no-activation protocols, and point-of-care manufacturing. These approaches have the advantage of a rapid turnaround while maintaining a less differentiated and exhausted phenotype. These efforts are leading to ultrarapid production methods and even elimination of ex vivo manipulation with the use of in vivo manufacturing approaches. In this Review, we focus on the advances needed to accelerate CAR T-cell manufacture (including near-patient methods), with an emphasis on improved therapeutic efficacy and rapid turnaround time, and simplified quality control procedures required to fully realise the clinical potential of CAR T-cell therapies.