Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity
Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity
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DOI：
10.1158/0008-5472.can-10-2884
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发表时间：
2010-12-01
期刊：
影响因子：
11.2
通讯作者：
Darcy, Phillip K.
中科院分区：
文献类型：
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作者：
Wang, Leanne X. J.;Westwood, Jennifer A.;Darcy, Phillip K.
涉及用抗原特异性嵌合单链受体对T细胞进行遗传修饰的连续性免疫疗法是用于治疗癌症的有前景的方法。为了确定基因修饰的T细胞是否可以诱导抗肿瘤作用而没有相关的自身免疫病理学，我们评估了表达抗Her-2嵌合受体的T细胞在Her-2转基因小鼠中根除肿瘤的能力，所述Her-2转基因小鼠在脑和乳腺组织中表达人Her-2作为自身抗原。在过继转移研究中，我们证明了与对照T细胞相比，给予抗Her-2 T细胞后，荷Her-2（+）24 JK肿瘤的小鼠的存活率显著改善。发现在过继转移抗Her-2 T细胞和施用IL-2之前并入淋巴清除步骤均进一步提高存活率。肿瘤生长的减少也与转移的T细胞在肿瘤部位的定位相关。此外，在用Her-2（+）肿瘤再激发后的长期存活小鼠中可以诱导抗原特异性回忆应答。重要的是，抗肿瘤作用与表达Her-2抗原的正常组织中的任何自身免疫病理学无关。这项研究强调了使用基因工程T细胞作为癌症安全有效治疗的治疗潜力。Cancer Res; 70（23）; 9591-8. (C)2010年AACR。
Adoptive immunotherapy involving genetic modification of T cells with antigen-specific, chimeric, single-chain receptors is a promising approach for the treatment of cancer. To determine whether gene-modified T cells could induce antitumor effects without associated autoimmune pathology, we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumor in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissues. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2(+) 24JK tumor following administration of anti-Her-2 T cells compared with control T cells. The incorporation of a lymphoablative step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 were both found to further enhance survival. The reduction in tumor growth was also correlated with localization of transferred T cells at the tumor site. Furthermore, an antigen-specific recall response could be induced in long-term surviving mice following rechallenge with Her-2(+) tumor. Importantly, antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment of cancer. Cancer Res; 70(23); 9591-8. (C) 2010 AACR.