Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma
Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma
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DOI：
10.1111/j.1365-2141.2010.08297.x
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发表时间：
2010-10-01
影响因子：
6.5
通讯作者：
Kimura, Akiro
中科院分区：
文献类型：
--
作者：
Mihara, Keichiro;Yanagihara, Kazuyoshi;Kimura, Akiro
利用人工受体，有可能将免疫细胞的特异性与肿瘤相关抗原重新定向，这有望为癌症免疫治疗提供一种有用的策略。鉴于B细胞非霍奇金淋巴瘤(B-NHL)细胞总是表达CD19和CD38，这些抗原可能是这种免疫治疗的合适分子候选。我们用抗CD19嵌合受体(CAR)或抗CD38-CAR(分别含有抗CD19和抗CD38抗体衍生的单链可变区)转导人外周T细胞或T细胞系。逆转录病毒转导使抗CD19-CAR或抗CD38-CAR在T细胞中高效表达(60%)。用抗CD19-CAR或抗CD38-CAR转导的T细胞株Hut78对B-NHL细胞株、HT和RL细胞以及从患者分离的淋巴瘤细胞具有较强的细胞毒作用。有趣的是，两种CARS的使用对体外培养的HT细胞都有相加的细胞毒作用。在联合利妥昔单抗的情况下，表达抗CD19-CAR或抗CD38-CAR的人外周T细胞增强了对异种移植小鼠的HT-荧光素酶细胞的细胞毒作用。此外，协同抑瘤活性在体内持续2个月以上。这些结果为临床测试利妥昔单抗与携带CAR的自体T细胞联合治疗侵袭性或复发性B-NHL提供了有力的理论基础。
P>Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (> 60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs.