肿瘤细胞治疗研究
英文原题：Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results.
Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results.
我们得出结论，GD2-CAR.15 NKT细胞是安全的，并且能够在NB患者中介导客观缓解。
Vα24不变自然杀伤T细胞（NKTs）具有抗肿瘤特性，可通过嵌合抗原受体（CARs）增强。本文报告了首次人体1期评估的最新中期结果，该评估在12例神经母细胞瘤（NB）患儿中测试了共表达GD2特异性CAR与白细胞介素15（IL15）的自体NKTs（GD2-CAR.15）。主要目标为安全性和确定最大耐受剂量（MTD）。抗肿瘤活性作为次要目标进行评估。免疫反应评估为额外目标。未发生剂量限制性毒性；1例患者出现2级细胞因子释放综合征，经托珠单抗治疗后缓解。未达到MTD。客观缓解率为25%（3/12），包括2例部分缓解和1例完全缓解。产品中CD62L+ NKTs的频率与患者体内CAR-NKT扩增相关，且在缓解者（n=5；客观缓解或疾病稳定伴肿瘤负荷减少）中高于非缓解者（n=7）。BTG1（BTG抗增殖因子1）表达在外周GD2-CAR.15 NKTs中上调，是耗竭NKT和T细胞低反应性的关键驱动因素。敲低BTG1的GD2-CAR.15 NKTs在小鼠模型中清除了转移性NB。我们得出结论：GD2-CAR.15 NKTs是安全的，可在NB患者中介导客观缓解。此外，其抗肿瘤活性可能通过靶向BTG1而增强。ClinicalTrials.gov注册号：NCT03294954。
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 .
MEMBER ACCOUNT
登录成功会直接打开下一页。
