Tisagenlecleucel, a CD19-specific autologous chimeric antigen receptor (CAR)-T cell therapy, is efficacious for the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia and diffuse large B-cell lymphoma. The tisagenlecleucel manufacturing process was initially developed in an academic setting and subsequently transferred to industry for qualification, validation and scaling up for global clinical trials and commercial distribution. Use of fresh leukapheresis material was recognized early on in the transfer process as a challenge with regard to establishing a global supply chain. To maximize manufacturing success rates and to overcome logistical challenges, cryopreservation was adapted into the Novartis manufacturing process from the beginning of clinical trials. Tisagenlecleucel manufactured in centralized facilities with cryopreserved leukapheresis material has been used successfully in global clinical trials at more than 50 clinical centers in 12 countries. Cryopreservation provides flexibility in scheduling leukapheresis when the patient's health is optimal to provide T cells; it also provides protection from external factors, such as shipping delays, and removes manufacturing time constraints. Several studies were performed to establish comparability of fresh versus cryopreserved leukapheresis material, to evaluate and optimize the cryopreservation process, to determine the optimal temperature and maximum hold time prior to cryopreservation and to determine the optimal temperature range for shipment and storage. Using the current validated industry manufacturing process, high success rates were achieved with regard to manufacturing tisagenlecleucel batches that met specifications and were released to patients. Consistent product quality and positive clinical outcomes support the use of cryopreserved non-mobilized peripheral mononuclear blood cells collected using leukapheresis for CAR-T cell manufacturing.

中文翻译：

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用于制造嵌合抗原受体-T 细胞的自体冷冻白细胞去除术细胞材料

Tisagenlecleucel 是一种 CD19 特异性自体嵌合抗原受体 (CAR)-T 细胞疗法，可有效治疗复发/难治性 B 细胞前体急性淋巴细胞白血病和弥漫性大 B 细胞淋巴瘤。tisagenlecleucel 制造工艺最初是在学术环境中开发的，随后转移到工业界，用于全球临床试验和商业分销的资格、验证和扩大规模。在转移过程的早期，使用新鲜的白细胞去除术材料被认为是建立全球供应链的挑战。为了最大限度地提高制造成功率并克服后勤方面的挑战，从临床试验开始就将冷冻保存应用于诺华的制造过程中。在集中设施中使用冷冻保存的白细胞去除术材料制造的 Tisagenlecleucel 已成功用于 12 个国家的 50 多个临床中心的全球临床试验。当患者的健康状况最佳以提供 T 细胞时，冷冻保存为安排白细胞去除术提供了灵活性；它还提供保护免受外部因素的影响，例如运输延迟，并消除制造时间限制。进行了多项研究以建立新鲜与冷冻保存的白细胞去除术材料的可比性，评估和优化冷冻保存过程，确定冷冻保存前的最佳温度和最长保持时间，并确定运输和储存的最佳温度范围。使用当前经过验证的行业制造工艺，在制造符合规格并发布给患者的 tisagenlecleucel 批次方面取得了很高的成功率。一致的产品质量和积极的临床结果支持使用通过白细胞去除术收集的冷冻保存的非动员外周单核血细胞用于 CAR-T 细胞制造。