Wang Qingqing, Yu Hai, Zhang Lihuang, Ju Dianwen, Pan Jianping, Xia Dajing, Yao Hangping, Zhang Weiping, Wang Jianli, Cao Xuetao
Institute of Immunology, Zhejiang University, 353 Yan'an Road, Hangzhou 310031, P.R. China.
J Mol Med (Berl). 2002 Sep;80(9):585-94. doi: 10.1007/s00109-002-0345-3. Epub 2002 Jun 4.
Bacterial superantigens are extremely potent activators of murine and human T lymphocytes. To engineer superantigens for cancer immunotherapy, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the human colon carcinoma-reactive monoclonal antibody (mAb) C215. Fusion protein C215Fab-SEA can trigger cytotoxic T cells against C215 antigen positive tumor cells and induce tumor-suppressive cytokines. However, the antitumor effect of C215Fab-SEA is often not satisfactory because of T cell deletion after activation and failure to induce potent CTL activity after repeated administration. Lymphotactin (Lptn) is a potent chemoattractant for T cells and NK cells. To improve the therapeutic efficacy of fusion protein C215Fab-SEA we investigated in this study the antitumor responses elicited by combination of C215Fab-SEA and adenovirus-mediated intratumoral Lptn gene transfer in the preestablished C215 antigen expressing B16 melanoma murine model. More significant inhibition of tumor growth and prolonged survival time were observed in tumor-bearing mice that received combined therapy of C215Fab-SEA and Ad-Lptn than those of mice treated with C215Fab-SEA or Ad-Lptn alone. The highest CTL activity of tumor-bearing mice was induced after combined therapy. Intratumoral coadministration of C215Fab-SEA and Ad-Lptn augmented splenic NK activity of tumor-bearing mice most markedly. Our data demonstrate that the in vivo antitumor effect of C215Fab-SEA immunotherapy is potentiated significantly by combination with intratumoral Lptn gene transfer through more efficient induction of specific and nonspecific antitumor immune responses.
细菌超抗原是鼠类和人类T淋巴细胞的极强激活剂。为了构建用于癌症免疫治疗的超抗原，将葡萄球菌肠毒素A（SEA）与人类结肠癌反应性单克隆抗体（mAb）C215的Fab区域进行基因融合。融合蛋白C215Fab-SEA可触发针对C215抗原阳性肿瘤细胞的细胞毒性T细胞并诱导肿瘤抑制性细胞因子。然而，由于激活后T细胞缺失以及重复给药后未能诱导出有效的CTL活性，C215Fab-SEA的抗肿瘤效果往往不尽人意。淋巴细胞趋化因子（Lptn）是T细胞和NK细胞的强效趋化剂。为了提高融合蛋白C215Fab-SEA的治疗效果，我们在本研究中调查了在预先建立的表达C215抗原的B16黑色素瘤小鼠模型中，C215Fab-SEA与腺病毒介导的瘤内Lptn基因转移联合使用所引发的抗肿瘤反应。与单独接受C215Fab-SEA或Ad-Lptn治疗的小鼠相比，接受C215Fab-SEA和Ad-Lptn联合治疗的荷瘤小鼠肿瘤生长受到更显著的抑制，生存时间延长。联合治疗后荷瘤小鼠诱导出最高的CTL活性。C215Fab-SEA与Ad-Lptn瘤内共同给药最显著地增强了荷瘤小鼠的脾脏NK活性。我们的数据表明，通过更有效地诱导特异性和非特异性抗肿瘤免疫反应，C215Fab-SEA免疫治疗与瘤内Lptn基因转移联合使用可显著增强其体内抗肿瘤效果。
