嵌合抗原受体修饰的T细胞的慢性 淋巴细胞白血病

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Chimeric AntigenReceptor–Modified T Cells in Chronic

Lymphoid Leukemia

嵌合抗原受体修饰的T细胞的慢性

淋巴细胞白血病

Abstract:

We designed a lentiviral vector expressing a chimericantigen receptor with specificity for the B-cell antigen CD19, coupled withCD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (asignal-transduction component of the T-cell antigen receptor) signalingdomains. A low dose (approximately 1.5×105 cells per kilogram of body weight)of autologous chimeric antigen receptor–modified T cells reinfused into apatient with refractory chronic lymphocytic leukemia (CLL) expanded to a levelthat was more than 1000 times as high as the initial engraftment level in vivo,with delayed development of the tumor lysis syndrome and with completeremission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxiceffect related to chimeric antigen receptor T cells was lymphopenia. Engineeredcells persisted at high levels for 6 months in the blood and bone marrow andcontinued to express the chimeric antigen receptor. A specific immune responsewas detected in the bone marrow, accompanied by loss of normal B cells and

leukemia cells that express CD19. Remission wasongoing 10 months after treatment.

摘要：

我们设计表达嵌合抗原受体具有特异性的B细胞抗原CD19识别能力，加上CD137和CD3-ζ信号域。低剂量（每公斤体重大约1.5×105个细胞）回输到难治性慢性淋巴细胞白血病（CLL）患者，患者的自体嵌合抗原受体修饰的T细胞扩张的水平是体内植入初期水平的1000多倍，并伴随着肿瘤溶解综合征的延迟开发和完全缓解。除了肿瘤溶解综合征，嵌合抗原受体的T细胞唯一的3/4级毒性作用是淋巴细胞。改造的细胞在血液和骨髓持续6个月的高浓度，并继续表达嵌合抗原受体。特定的免疫反应在骨髓中被检测，伴有正常B细胞和表达CD19白血病细胞的杀伤与损失。目前治疗10个月后可以得到缓解。