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.

中文翻译：

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加速和优化 CAR T 细胞生产，以提供更好的患者产品。


自体嵌合抗原受体 （CAR） T 细胞疗法改变了 B 细胞白血病和淋巴瘤的管理。然而，当前的制造流程存在物流障碍，限制了更广泛的应用。由于临床结果可能受到自体起始材料和生产工艺质量的严重影响，因此改善产品表型的策略至关重要。较短的制造过程具有更快地将产品带给患者的优势，同时避免了与长时间离体生产相关的高度分化和耗尽的 CAR T 细胞表型。本综述探讨了我们对有效 CAR T 细胞产品构成的理解以及提高产品质量的方法的进展。从历史上看，策略依赖于培养基成分的调整和分化程度较低的细胞亚型的选择。自 2020 年以来，该领域一直在转向减少扩增方案、无活化方案和即时生产。这些方法具有快速周转的优势，同时保持分化程度较低和耗竭的表型。这些努力导致了超快速的生产方法，甚至通过使用体内制造方法消除了离体操作。在本综述中，我们重点介绍加速 CAR T 细胞生产（包括近患者方法）所需的进展，重点是提高治疗效果和快速周转时间，以及简化充分实现 CAR T 细胞疗法临床潜力所需的质量控制程序。