Activated T-cell-mediated Immunotherapy With a Chimeric Receptor Against CD38 in B-cell Non-Hodgkin Lymphoma
Activated T-cell-mediated Immunotherapy With a Chimeric Receptor Against CD38 in B-cell Non-Hodgkin Lymphoma
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DOI：
10.1097/cji.0b013e3181adaff1
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发表时间：
2009-09-01
影响因子：
3.9
通讯作者：
Kimura, Akiro
中科院分区：
文献类型：
--
作者：
Mihara, Keichiro;Yanagihara, Kazuyoshi;Kimura, Akiro
利用嵌合抗原受体（CAR）的T细胞介导的免疫疗法预计将成为癌症的有力治疗方法。CD 38在B细胞非霍奇金淋巴瘤（B-NHL）细胞中高表达，是B-NHL免疫治疗的重要靶点。我们用抗CD 38-CAR逆转录病毒转导了几乎不表达CD 38的T细胞系Hut 78。将具有抗CD 38-CAR的Hut 78细胞与具有CD 38的B-NHL细胞系以及来自患者的B-NHL细胞共培养。4天后，大部分淋巴瘤细胞被杀死（细胞毒性水平> 95%）。相比之下，对CD 38阴性细胞系的细胞毒性不可检测。然后，我们将抗CD 38-CAR导入人外周血T细胞。然而，活细胞的回收率非常低，可能是因为抗CD 38-CAR与细胞表面上的CD 38缔合引起的所有自溶反应。抗CD 38抗体的加入可能通过阻断自溶反应而增加了活的转导T细胞的产量。我们将具有抗CD 38-CAR的人外周血T细胞与B-NHL细胞共培养。中位特异性细胞毒性大于90%。将这些细胞注射到NOD/SCID小鼠中4次，所述NOD/SCID小鼠接种有B-NHL细胞荧光素酶。在6只注射小鼠中的5只中，即使在接种后30天也检测不到荧光素酶活性。相比之下，它在所有注射模拟载体转导的T细胞的小鼠中增加。总之，具有抗CD 38-CAR的T细胞在体外和体内对B-NHL细胞显示出强大的细胞毒性。这些发现可能为改进T细胞介导的免疫治疗方法提供重要线索。
T-cell-mediated immunotherapy with a chimeric antigen receptor (CAR) is expected to become a powerful treatment for cancer. CD38, highly expressed in B-cell non-Hodgkin lymphoma (B-NHL) cells, is in attractive target in immunotherapy for B-NHL. We retrovirally transduced a T-cell line, Hut78, expressing little CD38, with an anti-CD38-CAR. Hut78 cells with the anti-CD38-CAR were cocultured with B-NHL cell lines hearing CD38 and also B-NHL cells from patients. Four days later most of the lymphoma cells were killed (the level of cytotoxicity was > 95%). By contrast, there was undetectable cytotoxicity against CD38-negative cell lines. Then, we introduced the anti-CD38-CAR into human peripheral T cells. However, the recovery of viable cells was very low, presumably because of all autolytic reaction caused by the association of the anti-CD38-CAR with CD38 on the cell surface. The addition of an anti-CD38 antibody increased the yield of viable transduced T cell probably by blocking the autolytic reaction. We cocultured human peripheral T cells hearing anti-CD38-CAR with B-NHL cells. The median specific cytotoxicity was greater than 90%. These cells were injected 4 times into NOD/SCID mice, which were inoculated with B-NHL cells luciferase. Luciferase activity was not detectable even 30 days after the inoculation in 5 of 6 mice injected. By contrast, it increased in all of the mice injected with the mock vector-transduced T cell. In conclusion, T cell with the anti-CD38-CAR showed powerful cytotoxicity against B-NHL cells in vitro and in vivo. These findings may provide all important Clue for improving the methodology of T-cell-mediated immunotherapy.