Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen
Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen
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DOI：
10.1111/j.1349-7006.2010.01734.x
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发表时间：
2010-12-01
期刊：
影响因子：
5.7
通讯作者：
Wakabayashi, Toshihiko
中科院分区：
文献类型：
--
作者：
Ohno, Masasuke;Natsume, Atsushi;Wakabayashi, Toshihiko
表皮生长因子受体变异体III(EGFRvIII)的同型常见于胶质母细胞瘤。在此之前，我们创造了特异性识别EGFRvIII的鼠单抗3C10(IgG2b)，以及3C10的重组单链可变区。目前这项研究的目的是开发被称为T小体的基因工程T细胞，它表达由3C10单链可变片段与CD3zeta(Zeta)链等信号模块耦合的嵌合受体，用于治疗表达突变的EGFR的肿瘤。成功构建嵌合3C10/CD3 Zeta T细胞受体后，用Western blotting和流式细胞术观察其在T小体上的表达。用干扰素-γELISPOT试验和标准的~(51)Cr释放细胞毒试验评价T抗体对EGFRvIII的特异性。此外，我们证明了系统递送的T小体渗透到脑内肿瘤并显著延缓了肿瘤的生长。这些结果表明，表达嵌合3C10/CD3 Zeta T细胞受体的T体能特异性识别表达EGFRvIII的胶质瘤细胞。综上所述，基于T小体的免疫疗法似乎是治疗胶质瘤的一种有前途的方法。(《癌症科学》2010；101：2518-2524)。
The isotype of epidermal growth factor receptor variant III (EGFRvIII) is often identified in glioblastomas. Previously, we created a mouse monoclonal antibody, 3C10 (IgG2b), that specifically recognized EGFRvIII, and a recombinant single-chain variable fragment of 3C10. The aim of the current study was to develop genetically engineered T cells, termed T-bodies, that express a chimeric receptor consisting of the 3C10 single-chain variable fragment coupled to signaling modules such as the CD3zeta (zeta) chain, for the treatment of tumors expressing mutant EGFR. After successful construction of the chimeric 3C10/CD3 zeta T-cell receptor, its expression on the T-body was observed using western blotting and flow cytometry. The specificity of the T-body for EGFRvIII was evaluated using an interferon-gamma Elispot assay and a standard 51Cr-release cytotoxicity assay. Furthermore, we demonstrated that the systemically delivered T-body infiltrated the intrabrain tumor and significantly delayed tumor growth. These results indicate that the T-body expressing the chimeric 3C10/CD3 zeta T-cell receptor specifically recognized glioma cells expressing EGFRvIII. In conclusion, T-body-based immunotherapy appears to be a promising approach for the treatment of glioma. (Cancer Sci 2010; 101: 2518-2524).