Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L⁺NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954.

Vα24 不变的自然杀伤 T 细胞 (NKT) 具有抗肿瘤特性，嵌合抗原受体 (CAR) 可以增强这种特性。在此，我们报告了对 12 名神经母细胞瘤 (NB) 儿童共表达 GD2 特异性 CAR 与白细胞介素 15 (IL15) (GD2-CAR.15) 的自体 NKT 的首次人体 1 期评估的最新中期结果。主要目标是安全性和最大耐受剂量（MTD）的确定。 GD2-CAR.15 NKT 的抗肿瘤活性作为次要目标进行评估。免疫反应评估是另一个目标。未发生剂量限制性毒性；一名患者经历了 2 级细胞因子释放综合征，但通过托珠单抗缓解。未达到 MTD。客观缓解率为25%（3/12），其中部分缓解2例，完全缓解1例。产品中 CD62L ⁺ NKT 的频率与患者的 CAR-NKT 扩增相关，并且应答者（ n = 5；客观缓解或疾病稳定，肿瘤负荷减少）高于无应答者（ n = 7）。 BTG1 （BTG 抗增殖因子 1）表达在外周 GD2-CAR.15 NKT 中上调，是耗尽的 NKT 和 T 细胞反应低下的关键驱动因素。敲低BTG1的 GD2-CAR.15 NKT 消除了小鼠模型中的转移性 NB。我们的结论是，GD2-CAR.15 NKT 是安全的，并且可以介导 NB 患者的客观反应。此外，它们的抗肿瘤活性可以通过靶向 BTG1 来增强。 ClinicalTrials.gov 注册：NCT03294954。