美国南加州大学Si-Yi Chen研究组研制了一种安全有效的抗CD19 CAR T细胞治疗方法。 2019年6月出版的《Nature Medicine》发表了这项成果。

该团队合成了一种新的抗CD19 CAR分子（CD19-BBz（86）），该分子来源于携带共刺激4-1BB和CD3ζ结构域的CD19-BBz原型。该课题组发现CD19-BBz(86)CAR T细胞产生低水平的细胞因子,表达高水平的凋亡分子并且扩散速度低于原型CD19-BBz CAR T细胞,尽管他们保留有效的溶细胞的活动。课题组人员对患有B细胞淋巴瘤的患者（ClinicalTrials.gov标识符NCT02842138）进行了CD19-BBz（86）CAR T细胞疗法的1期试验。11例中有6例完全缓解的(54.5%)，每例接受一个剂量的2 ×108 - 4 ×108 CD19-BBz(86)CART细胞。值得注意的是，在接受治疗的25例患者中，没有发生神经毒性或CRS(大于1级)。在接受CAR T细胞输注治疗的患者中，包括完全缓解的患者，血清细胞因子水平没有显著升高。CD19-BBz(86) CAR T细胞在体内持续增殖分化为记忆细胞。因此，使用新的CD19-BBz(86) CAR T细胞治疗产生了一个强有力的和持久的抗淋巴瘤反应，而不会引起神经毒性或严重的CRS，代表了一个安全有效的抗CD19 CAR T细胞治疗。

据了解，抗CD19嵌合抗原受体（CAR）T细胞疗法可以导致严重的细胞因子释放综合征（CRS）和神经毒性，阻碍其治疗应用。

附：英文原文

Title: A safe and potent anti-CD19 CAR T cell therapy

Author: Zhitao Ying, Xue F. Huang, Xiaoyu Xiang, Yanling Liu, Xi Kang, Yuqin Song, Xiaokai Guo, Hanzhi Liu, Ning Ding, Tingting Zhang, Panpan Duan, Yufu Lin, Wen Zheng, Xiaopei Wang, Ningjing Lin, Meifeng Tu, Yan Xie, Chen Zhang, Weiping Liu, Lijuan Deng, Shunyu Gao, Lingyan Ping, Xuejuan Wang, Nina Zhou, Junqing Zhang, Yulong Wang, Songfeng Lin, Mierzhati Mamuti, Xueyun Yu, Lizhu Fang, Shuai Wang, Haifeng Song, Guan Wang, Lindsey Jones, Jun Zhu, Si-Yi Chen

Issue&Volume: Volume 25 Issue 6，June 2019

Abstract: Anti-CD19 chimeric antigen receptor (CAR) T cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. Here we generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. We found that CD19-BBz(86) CAR T cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T cells, although they retained potent cytolytic activity. We performed a phase 1 trial of CD19-BBz(86) CAR T cell therapy in patients with B cell lymphoma (ClinicalTrials.gov identifier NCT02842138). Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2×108–4×108 CD19-BBz(86) CAR T cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. No significant elevation in serum cytokine levels after CAR T cell infusion was detected in the patients treated, including in those who achieved complete remission. CD19-BBz(86) CAR T cells persistently proliferated and differentiated into memory cells in vivo. Thus, therapy with the new CD19-BBz(86) CAR T cells produces a potent and durable antilymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T cell therapy.

DOI: 10.1038/s41591-019-0421-7

Source: https://www.nature.com/articles/s41591-019-0421-7