肿瘤细胞治疗研究
英文原题：CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.
CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.
嵌合抗原受体（CAR）T细胞疗法已经改变了血液肿瘤的治疗格局，然而疗效、持久性和安全性的差异无法仅用抗原选择或患者因素来解释。
嵌合抗原受体（CAR）T细胞疗法已经改变了血液肿瘤诊疗，但其疗效、持久性和安全性的差异不能仅用抗原选择或患者因素来解释。我们提出，生产平台是结局的主动生物学决定因素。所有获批产品均使用的病毒载体可提供稳定的基因组整合和持久表达，但受限于成本、载荷容量和集中化生产。非病毒策略，包括转座子、CRISPR敲入和信使RNA递送，可实现更快、更便宜且载荷更大的生产，同时引入不同的安全性和持续性特征。本综述提出一个三层机制框架，将生产重新界定为生物学：整合生物学决定基因组风险和转基因稳定性；克隆适应性塑造持续性、优势和耗竭；而受基因转移方法、细胞因子和培养应激影响的表观基因组印记，预先设定功能轨迹。临床观察将平台选择与免疫恢复联系起来，其中长期B细胞再生障碍和T细胞重建延迟导致感染相关非复发死亡，而单采时的造血储备成为一个实用预测指标。最后，生产被定位为细胞治疗民主化的关键。符合监管标准的去中心化非病毒生产可能实现公平可及，并推动CAR-T治疗从创新走向可持续的全球医疗。
Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.
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