Chimeric antigen receptor T cells for sustained remissions in leukemia.
Chimeric antigen receptor T cells for sustained remissions in leukemia.
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DOI：
10.1056/nejmoa1407222
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发表时间：
2014-10-16
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影响因子：
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通讯作者：
Grupp SA
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作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
复发性急性淋巴细胞白血病（ALL）是很难治疗的，尽管积极的治疗。靶向CD 19的嵌合抗原受体修饰的T细胞可以克服传统疗法的许多局限性，并在难治性疾病患者中诱导缓解。我们在复发性或难治性ALL患者中输注了用CD 19定向嵌合抗原受体（CTL 019）慢病毒载体转导的自体T细胞，剂量为0.76×106至20.6×106个CTL 019细胞/kg体重。监测患者的反应、毒性作用以及循环CTL 019 T细胞的扩增和持久性。共有30名儿童和成人接受了CTL 019。27例患者（90%）达到完全缓解，包括2例Blinatumomab难治性疾病患者和15例接受干细胞移植的患者。CTL 019细胞在体内增殖，并在有反应的患者的血液、骨髓和脑脊液中检测到。持续缓解的6个月无事件生存率为67%（95%置信区间[CI]，51 - 88），总生存率为78%（95% CI，65 - 95）。在6个月时，患者持续存在CTL 019的概率为68%（95% CI，50至92），患者无复发B细胞再生障碍的概率为73%（95% CI，57至94）。所有患者均出现麻黄碱释放综合征。27%的患者发生严重的阿托伐他汀释放综合征，与输注前较高的疾病负担相关，并可通过抗白细胞介素-6受体抗体托珠单抗有效治疗。针对CD 19的嵌合抗原受体修饰的T细胞治疗对复发和难治性ALL有效。CTL 019与高缓解率相关，即使在干细胞移植失败的患者中也是如此，并且观察到长达24个月的持久缓解。（由诺华和其他公司资助; CART 19 ClinicalTrials.gov编号，NCT 01626495和NCT 01029366。
Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×106 to 20.6×106 CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.)