使用 Sleeping Beauty 系统生成 CD19 特异性 CAR T 细胞的 I 期试验
Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells
研究目的是验证一种非病毒基因改造方法制备的 CAR T 细胞治疗 B 细胞恶性肿瘤是否安全。CAR T 细胞是经过基因改造、能识别肿瘤细胞的免疫细胞。研究人员利用 Sleeping Beauty 转座子系统（一种非病毒基因插入工具）将识别 CD19 的嵌合抗原受体导入 T 细胞，并在体外大量扩增。26 例晚期非霍奇金淋巴瘤和急性淋巴细胞白血病患者在造血干细胞移植后接受了这些 CAR T 细胞回输。结果显示，自体移植后 30 个月的无进展生存率为 83%，总生存率为 100%；异体移植后 12 个月分别为 53% 和 63%，未观察到急性或晚期毒性，也没有加重移植物抗宿主病。这表明该非病毒基因治疗方法安全性良好，值得进一步开展临床研发。
为什么推荐给您：非病毒转座子系统制备 CAR T 细胞首次用于人体，属新模态的早期阳性结果，但样本小、非随机。
不需要生物学背景，多打比方
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摘要Abstract
BACKGROUND: T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR.
METHODS: T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19).
RESULTS: SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.
CONCLUSIONS: CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.
TRIAL REGISTRATION: Autologous, NCT00968760; allogeneic, NCT01497184; long-term follow-up, NCT01492036.
FUNDING: National Cancer Institute, private foundations, and institutional funds. Please see Acknowledgments for details.