嵌合抗原受体修饰的T细胞治疗慢性淋巴细胞白血病

Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia

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.

嵌合抗原受体修饰的T细胞治疗慢性淋巴细胞白血病

我们设计了一个慢病毒载体，它表达B淋巴细胞抗原CD19，并且联合了CD137(T淋巴细胞中的共刺激受体[4-1BB]))和CD3-zeta（一种T细胞抗原受体信号转导元件）信号域。一个低剂量的自体嵌合抗原受体修饰的T细胞回输到一个难治性慢性淋巴细胞白血病患者（CLL）体内，扩增到体内初始水平的1000倍以上，延迟了肿瘤溶解综合征的发展和疾病完全缓解。除了肿瘤溶解综合症，唯一的其他占3/4的，与嵌合抗原受体相关的毒性作用是淋巴细胞减少。改造后的细胞在血液和骨髓中会持续存在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，伴随着表达CD19的正常B细胞和白血病细胞的损失。治疗之后，缓解持续10个月。低丙种球蛋白血症的治疗中会有一个预期的慢性毒性作用。