Molecular OncoSurgery Group, Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
Clin Cancer Res. 2012 Feb 15;18(4):1028-38. doi: 10.1158/1078-0432.CCR-11-2767. Epub 2012 Jan 6.
To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA.
Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)-positive pancreatic and prostate cancer cells.
Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced.
This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages.
为了增强 T 细胞对癌细胞的反应性，我们在淋巴细胞中过表达 TRAIL，因为这种死亡配体诱导肿瘤特异性凋亡。为了增加淋巴细胞与肿瘤细胞的接触时间，从而增加 TRAIL 与其死亡受体的接触时间，将淋巴细胞与双特异性抗体 EpCAMxCD3 的 CD3 臂连接，以引导淋巴细胞靶向肿瘤细胞中阳性表达癌症干细胞标志物 EpCAM/ESA 的细胞。
用 TRAIL 慢病毒转导淋巴细胞，并在体外和异种移植研究中评估 EpCAMxCD3 存在和不存在时的抗肿瘤作用，使用上皮细胞黏附分子（EpCAM）阳性的胰腺和前列腺癌细胞。
与对照淋巴细胞相比，TRAIL 淋巴细胞增加了细胞毒性，并进一步诱导了几种凋亡相关分子的表达。将 TRAIL 淋巴细胞和肿瘤细胞共移植到小鼠中，或在较大的异种移植瘤中经皮注射 TRAIL 淋巴细胞，可延缓肿瘤生长并诱导凋亡。TRAIL 淋巴细胞与 EpCAMxCD3 的联合使用通过增强抗凋亡和抗增殖信号以及减少肿瘤血管生成来增强肿瘤清除作用。涉及并与增强趋化因子分泌和小鼠巨噬细胞浸润相关的肿瘤内囊肿形成，提示炎症宿主反应的贡献。最重要的是，对常规化疗具有耐药性的具有癌症干细胞特征的胰腺癌细胞的致瘤性被强烈降低。
这种基因免疫治疗方法可能是一种新的工具，即使在癌症的晚期也可以支持内源性免疫反应。
