用于白血病持续缓解的嵌合抗原受体T细胞。
Chimeric antigen receptor T cells for sustained remissions in leukemia.
作者信息
Maude Shannon L, Frey Noelle, Shaw Pamela A, Aplenc Richard, Barrett David M, Bunin Nancy J, Chew Anne, Gonzalez Vanessa E, Zheng Zhaohui, Lacey Simon F, Mahnke Yolanda D, Melenhorst Jan J, Rheingold Susan R, Shen Angela, Teachey David T, Levine Bruce L, June Carl H, Porter David L, Grupp Stephan A
机构信息
From the Division of Oncology, Children's Hospital of Philadelphia (S.L.M., R.A., D.M.B., N.J.B., S.R.R., D.T.T., S.A.G.), the Departments of Pediatrics (S.L.M., R.A., D.M.B., N.J.B., S.R.R., D.T.T., S.A.G.), Biostatistics and Epidemiology (P.A.S., R.A.), and Pathology and Laboratory Medicine (J.J.M., B.L.L., C.H.J., S.A.G.), the Division of Hematology-Oncology (N.F., D.L.P.), and Abramson Cancer Center (N.F., A.C., V.E.G., Z.Z., S.F.L., Y.D.M., J.J.M., B.L.L., C.H.J., D.L.P., S.A.G.), Perelman School of Medicine, University of Pennsylvania - all in Philadelphia; and Novartis Pharmaceuticals, East Hanover, NJ (A.S.).
出版信息
N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222.
BACKGROUND
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.
METHODS
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 0.76×10(6) to 20.6×10(6) 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.
RESULTS
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.
CONCLUSIONS
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.).
背景
尽管有积极的治疗方法，但复发性急性淋巴细胞白血病（ALL）仍难以治疗。靶向CD19的嵌合抗原受体修饰的T细胞可能克服传统疗法的许多局限性，并诱导难治性疾病患者缓解。
方法
我们以每千克体重0.76×10⁶至20.6×10⁶个CTL019细胞的剂量，向复发或难治性ALL患者输注用CD19导向的嵌合抗原受体（CTL019）慢病毒载体转导的自体T细胞。对患者进行反应、毒性作用以及循环CTL019 T细胞的扩增和持久性监测。
结果
共有30名儿童和成人接受了CTL019治疗。27例患者（90%）实现完全缓解，其中包括2例对blinatumomab难治的疾病患者和15例接受过干细胞移植的患者。CTL019细胞在体内增殖，在有反应的患者的血液、骨髓和脑脊液中可检测到。实现了持续缓解，6个月无事件生存率为67%（95%置信区间[CI]，51至88），总生存率为78%（95%CI，65至95）。在6个月时，患者体内CTL019持续存在的概率为68%（95%CI，50至92），无复发B细胞发育不全的概率为73%（95%CI，57至94）。所有患者均出现细胞因子释放综合征。27%的患者发生严重细胞因子释放综合征，这与输注前较高的疾病负担相关，并可用抗白细胞介素-6受体抗体托珠单抗有效治疗。
结论
针对CD19的嵌合抗原受体修饰的T细胞疗法在治疗复发和难治性ALL方面有效。CTL019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。（由诺华公司及其他机构资助；CART19 ClinicalTrials.gov编号，NCT01626495和NCT01029366。）
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