肿瘤细胞治疗研究
英文原题：GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial.
GD2-targeting CAR T cells in high-risk neuroblastoma: a phase 1/2 trial.
我们现在报告在所有 35 例入组患者以及 19 例按试验相同标准筛选并在医院豁免环境下接受治疗的额外儿童中获得的最终结果。
针对双唾液酸神经节苷脂 GD2 的第三代 CAR-T（GD2-CART01），在 I/II 期临床试验中期分析中显示出治疗高危转移性、复发或难治性神经母细胞瘤儿童的良好疗效。本文报告试验纳入的全部 35 例患者及另 19 例按同一标准筛选、在医院豁免机制下接受治疗儿童的最终结果。试验主要终点为安全性、最大耐受剂量、客观缓解率（ORR）及不同时间点的完全缓解率；次要终点包括 5 年总生存期（OS）和 GD2-CART01 持续存在情况。未发现新的安全性信号。4 名儿童发生 3 级免疫效应细胞相关神经毒性综合征，通过 rimiducid 激活诱导型 caspase-9 自杀基因后迅速控制。最大耐受剂量为每千克 10 × 10⁶ 个 CAR⁺ 细胞。临床试验队列 ORR 为 66%（21/32；排除 3 例无可测量疾病患者）。完全缓解率在 6 周、3 个月和 6 个月时分别为 37%、34% 和 40%。临床试验患者中，64% 的 GD2-CART01 持续存在 12 个月。中位随访 4.2 年时，试验队列 5 年 OS 为 42.67%。总共 54 名儿童中有 38 名在低肿瘤负荷时接受每千克 10 × 10⁶ 个 GD2-CART01（定义为目标人群），其中 8 名患者在一线治疗后达到无可测量疾病状态并接受巩固治疗。目标人群 ORR 为 77%，5 年 OS 和无事件生存率分别为 68% 和 53%。在接受 1 或 2 线治疗后即接受治疗的患者中，5 年 OS 和无事件生存显著优于接受 3 线治疗后才治疗者。诊断时即采集淋巴细胞的患者结局更好。结果证实，GD2-CART01 可使高危转移性、复发或难治性神经母细胞瘤儿童获得持久缓解。ClinicalTrials.gov 编号：NCT03373097。
Antidisialoganglioside (GD2), third-generation chimeric antigen receptor (CAR) T cells (GD2-CART01) have shown encouraging efficacy in children with high-risk metastatic, relapsed, or refractory neuroblastoma in the interim analysis of a phase 1/2 clinical trial. We now present the final results obtained in all 35 patients enrolled and in 19 additional children selected with the same criteria of the trial and treated in a hospital exemption setting. Primary endpoints for the trial were safety, maximum tolerated dose, overall response rate (ORR) and complete remission rate at various timepoints. Secondary endpoints included 5-year overall survival (OS) and persistence of GD2-CART01. No new safety signals were observed. Grade 3 immune effector cell-associated neurotoxicity syndrome was diagnosed in four children and rapidly controlled with the activation of the inducible caspase-9 suicide gene by rimiducid. The maximum tolerated dose was 10 10 6 CAR + cells per kg. The ORR of the patients enrolled in the clinical trial was 66% (21/32-excluding the three patients treated in nonevidence of disease). The complete remission rate at 6 weeks, 3 months and 6 months reached 37%, 34% and 40%, respectively. GD2-CART01 persisted 12 months in 64% of the patients enrolled in the clinical trial. With a median follow-up of 4.2 years, the 5-year OS for the trial cohort was 42.67%. In total, 38 of 54 children were treated with low disease burden at 10 10 6 GD2-CART01 cells per kg (defined as the target population), including eight patients consolidated in nonevidence of disease after the first line. The ORR in the target population was 77%, the 5-year OS and event-free survivals were 68% and 53%, respectively. Substantially superior 5-year OS and event-free survivals were observed in patients treated after one or two lines of therapy versus those treated after 3 lines of therapy. Better results were observed in patients whose lymphocyte collection was performed at the time of diagnosis. These results confirm that GD2-CART01 can induce durable remissions in children with high-risk metastatic, relapsed, or refractory neuroblastoma. ClinicalTrials.gov identifier: NCT03373097 .
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