Altenschmidt U, Klundt E, Groner B
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
J Immunol. 1997 Dec 1;159(11):5509-15.
Adoptive immunotherapy of cancer uses the transfer of tumor-reactive immune cells. The success of this procedure is dependent upon the specificity of the transferred immune cells, their number, and their ability to reach their target cells. We genetically modified T lymphocytes and equipped them with the ability to specifically recognize tumor cells. Tumor cells overexpressing the ErbB-2 receptor served as a model. The target cell recognition specificity is conferred to T lymphocytes by transduction of a chimeric gene encoding the zeta-chain of the TCR and a single chain antibody (scFv(FRP5)) directed against the human ErbB-2 receptor. The chimeric scFv(FRP5)-zeta gene was introduced into primary mouse T lymphocytes via retroviral gene transfer. Naive T lymphocytes were activated and infected by cocultivation with a retrovirus-producing packaging cell line. The scFv(FRP5)-zeta fusion gene was expressed in >75% of the T cells. These T cells lysed ErbB-2-expressing target cells in vitro with high specificity. We tested the antitumor efficacy of scFv(FRP5)-zeta-expressing T cells in a syngeneic BALB/c model. The mice were treated with autologous, transduced T cells. The adoptively transferred scFv(FRP5)-zeta-expressing T cells caused total regression of ErbB-2-expressing tumors. The presence of the transduced T lymphocytes in the tumor tissue was monitored. No humoral response directed against the transduced T cells was observed. Abs directed against the ErbB-2 receptor were detected upon tumor lysis.
癌症的过继性免疫疗法采用肿瘤反应性免疫细胞的转移。该方法的成功取决于所转移免疫细胞的特异性、数量及其到达靶细胞的能力。我们对T淋巴细胞进行基因改造，使其具备特异性识别肿瘤细胞的能力。过表达ErbB-2受体的肿瘤细胞用作模型。通过转导编码TCR ζ链和针对人ErbB-2受体的单链抗体（scFv(FRP5)）的嵌合基因，将靶细胞识别特异性赋予T淋巴细胞。通过逆转录病毒基因转移将嵌合scFv(FRP5)-ζ基因导入原代小鼠T淋巴细胞。通过与产生逆转录病毒的包装细胞系共培养激活并感染未致敏的T淋巴细胞。scFv(FRP5)-ζ融合基因在超过75%的T细胞中表达。这些T细胞在体外以高特异性裂解表达ErbB-2的靶细胞。我们在同基因BALB/c模型中测试了表达scFv(FRP5)-ζ的T细胞的抗肿瘤功效。用自体转导的T细胞治疗小鼠。过继转移的表达scFv(FRP5)-ζ的T细胞使表达ErbB-2的肿瘤完全消退。监测肿瘤组织中转导T淋巴细胞的存在情况。未观察到针对转导T细胞的体液反应。肿瘤裂解时检测到针对ErbB-2受体的抗体。
