GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma
GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma
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DOI：
10.1056/nejmoa2210859
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发表时间：
2023-04-06
影响因子：
158.5
通讯作者：
Locatelli, Franco
中科院分区：
文献类型：
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作者：
Del Bufalo, Francesca;De Angelis, Biagio;Locatelli, Franco
研究背景针对肿瘤细胞上表达的二唾液酸神经节苷脂GD 2的嵌合抗原受体（CAR）表达T细胞的免疫疗法可能是高危神经母细胞瘤患者的治疗选择。（1至25岁）复发性或难治性，高风险神经母细胞瘤，以测试自体，表达诱导型caspase 9自杀基因的第三代GD 2-CAR T细胞（GD 2-CART 01）.共27例接受过大量预治疗的神经母细胞瘤儿童（12例患有难治性疾病，14例患有复发性疾病，和1例在一线治疗结束时完全缓解）入组并接受GD 2-CART 01。未观察到生成GD 2-CART 01失败。在试验的I期部分中测试了三个剂量水平（3、6和10 × 10（6）CAR阳性T细胞/千克体重），未记录到剂量限制性毒性作用;试验的II期部分的推荐剂量为10 × 10（6）CAR阳性T细胞/千克。27例患者中有20例（74%）发生细胞因子释放综合征，20例患者中有19例（95%）为轻度。在1例患者中，自杀基因被激活，GD 2CART 01快速消除。靶向GD 2的CAR T细胞在体内扩增，并且在输注后长达30个月的27名患者中的26名患者的外周血中可检测到（中位持续时间为3个月;范围为1至30）。17名儿童对治疗有反应（总体反应，63%）; 9名患者完全反应，8名患者部分反应。在接受推荐剂量的患者中，3年总生存率和无事件生存率分别为60%和36%。与治疗相关的毒性作用发展，自杀基因的激活控制副作用。GD 2-CART 01可能具有持续的抗肿瘤作用。
BACKGROUNDImmunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma.METHODSIn an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01).RESULTSA total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10x10(6) CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10x10(6) CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively.CONCLUSIONSThe use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect.