Willemsen R A, Weijtens M E, Ronteltap C, Eshhar Z, Gratama J W, Chames P, Bolhuis R L
Department of Clinical and Tumor Immunology, Academic Hospital Rotterdam/Daniel den Hoed Cancer Center, The Netherlands.
Gene Ther. 2000 Aug;7(16):1369-77. doi: 10.1038/sj.gt.3301253.
Primary human activated T lymphocytes were genetically grafted with chimeric T cell receptors (TCR). Three domain single chain (sc-) TCR as well as two chain (tc-) TCR gene constructs were derived from the melanoma-specific cytotoxic human T cell (CTL) clone 82/30, and linked to the CD3-zeta signaling element. Chimeric TCR alpha and beta receptor genes were structurally designed to prevent pairing with endogenous TCR alpha and beta chains in order to prevent the generation of unpredictable immune specificities. After transduction of polyclonally activated human peripheral blood lymphocytes with retroviral vectors harboring the chimeric receptor genes, genetically engineered cells specifically recognized and responded to MAGE-A1POS/HLA-A1POS cells. Importantly, each type of transduced T lymphocytes that bound specifically to peptide/MHC complexes also showed specific antitumor reactivity as well as lymphokine production. Genetically engineered primary human T lymphocytes expressing chimeric sc- or tc-TCR therefore hold promise for disease-specific therapies.
将嵌合型T细胞受体（TCR）基因移植到原代人活化T淋巴细胞中。三结构域单链（sc-）TCR以及双链（tc-）TCR基因构建体源自黑色素瘤特异性细胞毒性人T细胞（CTL）克隆82/30，并与CD3-zeta信号元件相连。嵌合型TCRα和β受体基因在结构上进行了设计，以防止与内源性TCRα和β链配对，从而避免产生不可预测的免疫特异性。在用携带嵌合受体基因的逆转录病毒载体转导多克隆活化的人外周血淋巴细胞后，基因工程细胞能够特异性识别MAGE-A1阳性/HLA-A1阳性细胞并对其作出反应。重要的是，每种与肽/MHC复合物特异性结合的转导T淋巴细胞类型也显示出特异性抗肿瘤反应以及淋巴因子产生。因此，表达嵌合型sc-TCR或tc-TCR的基因工程原代人T淋巴细胞有望用于疾病特异性治疗。
