Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
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DOI：
10.1056/nejmoa1103849
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发表时间：
2011-08-25
期刊：
影响因子：
--
通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Porter DL;Levine BL;Kalos M;Bagg A;June CH
我们设计了一种慢病毒载体，表达对B细胞抗原CD 19具有特异性的嵌合抗原受体，与CD 137（T细胞中的共刺激受体[4-1BB]）和CD 3-zeta（T细胞抗原受体的信号转导组分）信号传导结构域偶联。将低剂量（约1.5×105个细胞/千克体重）的自体嵌合抗原受体修饰的T细胞回输至难治性慢性淋巴细胞白血病（CLL）患者体内，扩增至体内初始植入水平的1000倍以上，肿瘤溶解综合征的发生延迟，并完全缓解。除肿瘤溶解综合征外，与嵌合抗原受体T细胞相关的唯一其他3/4级毒性作用是淋巴细胞减少症。工程细胞在血液和骨髓中持续高水平6个月，并继续表达嵌合抗原受体。在骨髓中检测到特异性免疫应答，伴随着表达CD 19的正常B细胞和白血病细胞的丢失。治疗后10个月持续缓解。低丙种球蛋白血症是一种预期的慢性毒性效应。
We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×105 cells per kilogram of body weight) of autologous chimeric antigen receptor–modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.