Thirty years after initial publications of the concept of a chimeric antigen receptor (CAR), the U.S. Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell therapy. Unlike other immunotherapies, such as immune checkpoint inhibitors and bispecific antibodies, CAR T cells are unique as they are "living drugs," that is, gene-edited killer cells that can recognize and kill cancer. During these 30 years of development, the CAR construct, T-cell manufacturing process, and clinical patient management have gone through rounds of failures and successes that drove continuous improvement. Tisagenlecleucel was the first gene therapy to receive approval from the FDA for any indication. The initial approval was for relapsed or refractory (r/r) pediatric and young-adult B-cell acute lymphoblastic leukemia in August 2017 and in May 2018 for adult r/r diffuse large B-cell lymphoma. Here we review the preclinical and clinical development of what began as CART19 at the University of Pennsylvania and later developed into tisagenlecleucel.

中文翻译：

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首个获得 FDA 批准的基因疗法的漫长道路：靶向 CD19 的嵌合抗原受体 T 细胞


在嵌合抗原受体 (CAR) 概念首次发表 30 年后，美国食品和药物管理局 (FDA) 批准了第一个抗 CD19 CAR T 细胞疗法。与免疫检查点抑制剂和双特异性抗体等其他免疫疗法不同，CAR T细胞是独特的，因为它们是“活体药物”，即可以识别和杀死癌症的基因编辑杀伤细胞。在这30年的发展过程中，CAR构建、T细胞制造工艺和临床患者管理经历了一轮又一轮的失败和成功，推动着不断改进。 Tisagenlecleucel 是第一个获得 FDA 批准用于任何适应症的基因疗法。最初批准于 2017 年 8 月用于治疗复发或难治性 (r/r) 儿童和年轻成人 B 细胞急性淋巴细胞白血病，并于 2018 年 5 月批准用于治疗成人 r/r 弥漫性大 B 细胞淋巴瘤。在这里，我们回顾了最初在宾夕法尼亚大学开发的 CART19，后来发展为 tisagenlecleucel 的临床前和临床开发。