PDF(Pubmed)
Abstract：
There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .
摘要：
迫切需要安全的同种异体嵌合抗原受体（CAR）免疫细胞疗法，有效和负担得起。我们在37例CD19B细胞恶性肿瘤患者中进行了表达抗CD19嵌合抗原受体和白介素15（CAR19/IL-15）的脐带血来源的自然杀伤（NK）细胞的1/2期试验。主要目标是安全性和有效性，定义为第30天总体反应(OR)。次要目标包括第100天的反应，无进展生存期,总体生存率和CAR19/IL-15NK细胞持久性。没有明显的毒性，如细胞因子释放综合征，观察到神经毒性或移植物抗宿主病.第30天和第100天的OR率为48.6%。1年总生存率和无进展生存率分别为68%和32%。分别。达到OR的患者的CAR-NK细胞水平更高，持续时间更长。从有核红细胞≤8×107的脐带血单元（CBU）接受CAR-NK细胞和收集至冷冻保存时间≤24h是最佳结果的最重要预测因素。来自这些最佳CBUs的NK细胞具有高度功能并且富含效应相关基因。相比之下,来自次优CBUs的NK细胞有炎症上调，缺氧和细胞应激程序。最后,使用多个鼠标模型，我们证实了来自体内最佳CBUs的CAR/IL-15NK细胞具有优异的抗肿瘤活性。这些发现揭示了CAR-NK细胞生物学的新特征，并强调了供体选择对同种异体细胞治疗的重要性。ClinicalTrials.gov标识符：NCT03056339。
