Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia
Successful application of anti-CD19 CAR-T therapy with IL-6 knocking down to patients with central nervous system B-cell acute lymphocytic leukemia
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敲低IL-6的抗CD19 CAR-T疗法成功应用于中枢神经系统B细胞急性淋巴细胞白血病患者
DOI：
10.1016/j.tranon.2020.100838
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发表时间：
2020-11-01
影响因子：
5
通讯作者：
Sun, Ai-Ning
中科院分区：
文献类型：
--
作者：
Chen, Li-Yun;Kang, Li-Qing;Sun, Ai-Ning
很少有研究描述了嵌合抗原受体修饰的T细胞（CAR-T）治疗中枢神经系统（CNS）B细胞急性淋巴细胞白血病（B-ALL）患者，原因是危及生命的CAR-T相关脑病（克雷斯）安全性问题。在本研究中，制备了利用短发夹RNA（shRNA）-IL-6基因沉默技术靶向CD 19的CAR-T（ssCART-19 s）。我们进行了1期临床试验（ClinicalTrials.gov编号，NCT 03064269）。入组了3例复发性CNS B-ALL患者，用氟达拉滨和环磷酰胺进行淋巴细胞清除预处理，并连续3天输注ssCART-19。监测临床症状和实验室检查。ssCART-19治疗后，3名患者的症状几乎完全缓解。MRI显示白血病脑浸润明显减少，脑脊液中未见白血病原始细胞，细胞学和分子生物学检查证实。此外，在所有患者的CSF中观察到细胞因子和免疫细胞水平的增加。在患者中仅观察到1级细胞因子释放综合征（CRS），表现为发热。总之，具有shRNA-IL-6基因敲低的CAR-Ts迁移到CNS中，根除了白血病细胞，并升高了CSF中的细胞因子，具有轻度、可接受的副作用。
Few studies have described chimeric antigen receptor-modified T cell (CAR-T) therapy for central nervous system (CNS) B-cell acute lymphocytic leukemia (B-ALL) patients due to life-threatening CAR-T-related encephalopathy (CRES) safety issues. In this study, CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) were prepared. We conducted a phase 1 clinical trial (ClinicalTrials.gov number, NCT03064269). Three patients with relapsed CNS B-ALL were enrolled, conditioned with the fludarabine and cyclophosphamide for lymphocyte depletion and infused with ssCART-19s for three consecutive days. Clinical symptoms and laboratory examinations were monitored. After ssCART-19 treatment, three patients' symptoms resolved almost entirely. Brain leukemic infiltration reduced significantly based on magnetic resonance imaging (MRI), and there were no leukemic blasts in cerebrospinal fluid (CSF), which was confirmed by cytological and molecular examinations. Additionally, increases in the levels of cytokines and immune cells were observed in the CSF of all patients. Only grade 1 cytokine release syndrome (CRS) manifesting as fever was noted in patients. In conclusion, CAR-Ts with shRNA-IL-6 gene knockdown migrated into the CNS, eradicated leukemic cells and elevated cytokines in CSF with mild, acceptable side effects.