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Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results
Nature Medicine ( IF 58.7 ) Pub Date : 2023-05-15 , DOI: 10.1038/s41591-023-02363-y
Andras Heczey 1, 2 , Xin Xu 1 , Amy N Courtney 1 , Gengwen Tian 1 , Gabriel A Barragan 1 , Linjie Guo 1 , Claudia Martinez Amador 1 , Nisha Ghatwai 1 , Purva Rathi 1 , Michael S Wood 1 , Yanchuan Li 1 , Chunchao Zhang 1 , Thorsten Demberg 1 , Erica J Di Pierro 1 , Andrew C Sher 3 , Huimin Zhang 2 , Birju Mehta 2 , Sachin G Thakkar 2 , Bambi Grilley 2 , Tao Wang 4 , Brian D Weiss 5 , Antonino Montalbano 6 , Meena Subramaniam 6 , Chenling Xu 6 , Chirag Sachar 6 , Daniel K Wells 6 , Gianpietro Dotti 7 , Leonid S Metelitsa 1, 2
Affiliation  

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.



中文翻译:


复发性或难治性神经母细胞瘤中的抗 GD2 CAR-NKT 细胞:更新的 1 期试验中期结果



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。

更新日期:2023-05-16
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