Abramson Cancer Center, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
N Engl J Med. 2011 Aug 25;365(8):725-33. doi: 10.1056/NEJMoa1103849. Epub 2011 Aug 10.
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 1.5×10(5) 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.
我们设计了一种慢病毒载体，表达了一种针对 B 细胞抗原 CD19 的嵌合抗原受体，该受体与 CD137（T 细胞中的共刺激受体[4-1BB]）和 CD3-ζ（T 细胞抗原受体的信号转导成分）信号结构域相连。将低剂量（约每千克体重 1.5×10(5)个细胞）的自体嵌合抗原受体修饰的 T 细胞再输注到难治性慢性淋巴细胞白血病（CLL）患者体内，这些细胞在体内的扩增水平超过初始植入水平的 1000 倍以上，肿瘤溶解综合征的发展延迟，并且完全缓解。除了肿瘤溶解综合征，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存在 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反应，同时正常表达 CD19 的 B 细胞和白血病细胞丢失。治疗 10 个月后仍处于缓解期。低丙种球蛋白血症是一种预期的慢性毒性作用。
