Vigna Elisa, Pacchiana Giovanni, Mazzone Massimiliano, Chiriaco Cristina, Fontani Lara, Basilico Cristina, Pennacchietti Selma, Comoglio Paolo M
Laboratory for Gene Transfer and Therapy,Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Turin, Italy.
Cancer Res. 2008 Nov 15;68(22):9176-83. doi: 10.1158/0008-5472.CAN-08-1688.
Gene therapy provides a still poorly explored opportunity to treat cancer by "active" immunotherapy as it enables the transfer of genes encoding antibodies directed against specific oncogenic proteins. By a bidirectional lentiviral vector, we transferred the cDNA encoding the heavy and light chains of a monoclonal anti-Met antibody (DN-30) to epithelial cancer cells. In vitro, the transduced cells synthesized and secreted correctly assembled antibodies with the expected high affinity, inducing down-regulation of the Met receptor and strong inhibition of the invasive growth response. The inhibitory activity resulted (a) from the interference of the antibody with the Met receptor intracellular processing ("cell autonomous activity," in cis) and (b) from the antibody-induced cleavage of Met expressed at the cell surface ("bystander effect," in trans). The monoclonal antibody gene transferred into live animals by systemic administration or by local intratumor delivery resulted in substantial inhibition of tumor growth. These data provide proof of concept both for targeting the Met receptor and for a gene transfer-based immunotherapy strategy.
基因治疗为通过“主动”免疫疗法治疗癌症提供了一个尚未得到充分探索的机会，因为它能够转移编码针对特定致癌蛋白的抗体的基因。我们通过双向慢病毒载体将编码单克隆抗Met抗体（DN-30）重链和轻链的cDNA转移到上皮癌细胞中。在体外，转导的细胞合成并分泌出正确组装的具有预期高亲和力的抗体，导致Met受体下调并强烈抑制侵袭性生长反应。抑制活性产生于：（a）抗体对Met受体细胞内加工过程的干扰（“顺式细胞自主活性”），以及（b）抗体诱导细胞表面表达的Met的裂解（“反式旁观者效应”）。通过全身给药或局部瘤内递送将单克隆抗体基因导入活体动物后，可显著抑制肿瘤生长。这些数据为靶向Met受体和基于基因转移的免疫治疗策略提供了概念验证。
