Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis
Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis
复制标题
DOI：
10.1038/s41591-020-1074-2
复制
发表时间：
2020-10-12
期刊：
影响因子：
82.9
通讯作者：
Metelitsa, Leonid S.
中科院分区：
文献类型：
--
作者：
Heczey, Andras;Courtney, Amy N.;Metelitsa, Leonid S.
V α 24不变的自然杀伤T（NKT）细胞在小鼠肿瘤模型中显示出有效的抗肿瘤特性，并与癌症患者的良好结局有关。然而，这些细胞在人体中的数量很少，阻碍了它们的临床应用。在这里，我们报告了在复发性或耐药性神经母细胞瘤儿童中共表达GD 2特异性嵌合抗原受体（CAR）和白细胞介素-15的自体NKT细胞的1期剂量递增试验（NCT 03294954）中，所有3例剂量水平1入组患者的中期结果。主要和次要目的分别是评估安全性和抗肿瘤应答，免疫应答评价是额外目的。我们离体扩增了高纯度的NKT细胞（平均值+/- s.d.，94.7+/- 3.8%），并在环磷酰胺/氟达拉滨（Cy/Flu）淋巴细胞清除预处理后，以每平方米体表面积3 x 10（6）个CAR-NKT细胞治疗患者。Cy/Flu预处理是3-4级血液学不良事件的可能原因，因为它们发生在CAR-NKT细胞输注之前，并且没有观察到剂量限制性毒性。CAR-NKT细胞在体内扩增，定位于肿瘤，并且在一名患者中诱导了客观反应，骨转移病灶消退。这些初步结果表明，CAR-NKT细胞可以扩大到临床规模，并安全地应用于治疗癌症患者。在神经母细胞瘤患者的首次人体I期试验的中期分析中，高纯度GD 2特异性CAR-NKT细胞耐受性良好，没有观察到剂量限制性毒性。
V alpha 24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean +/- s.d., 94.7 +/- 3.8%) and treated patients with 3 x 10(6)CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.In an interim analysis of a first-in-human phase 1 trial of patients with neuroblastoma, highly pure GD2-specific CAR-NKT cells were well tolerated with no observed dose-limiting toxicities.