Cancer Gene Therapy Group, Department of Pathology and Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
Int J Cancer. 2015 Mar 1;136(5):1065-72. doi: 10.1002/ijc.29068. Epub 2014 Jul 10.
Oncolytic Western Reserve strain vaccinia virus selective for epidermal growth factor receptor pathway mutations and tumor-associated hypermetabolism was armed with human granulocyte-macrophage colony-stimulating factor (GMCSF) and a tdTomato fluorophore. As the assessment of immunological responses to human transgenes is challenging in the most commonly used animal models, we used immunocompetent Syrian golden hamsters, known to be sensitive to human GMCSF and semipermissive to vaccinia virus. Efficacy was initially tested in vitro on various human and hamster cell lines and oncolytic potency of transgene-carrying viruses was similar to unarmed virus. The hGMCSF-encoding virus was able to completely eradicate subcutaneous pancreatic tumors in hamsters, and to fully protect the animals from subsequent rechallenge with the same tumor. Induction of specific antitumor immunity was also shown by ex vivo co-culture experiments with hamster splenocytes. In addition, histological examination revealed increased infiltration of neutrophils and macrophages in GMCSF-virus-treated tumors. These findings help clarify the mechanism of action of GMCSF-armed vaccinia viruses undergoing clinical trials.
携带人粒细胞-巨噬细胞集落刺激因子（GMCSF）和 tdTomato 荧光蛋白的表皮生长因子受体通路突变和肿瘤相关高代谢选择的溶瘤性西方储备株痘苗病毒被武装。由于在最常用的动物模型中评估对人源转基因的免疫反应具有挑战性，我们使用免疫活性的叙利亚金黄地鼠进行研究，已知其对人源 GMCSF 敏感且对半许可的痘苗病毒敏感。最初在各种人和仓鼠细胞系上进行了体外功效测试，携带转基因的病毒的溶瘤效力与无武装病毒相似。携带 hGMCSF 基因的病毒能够完全根除仓鼠皮下胰腺肿瘤，并完全保护动物免受相同肿瘤的后续再挑战。通过与仓鼠脾细胞的体外共培养实验也证明了诱导特异性抗肿瘤免疫。此外，组织学检查显示 GMCSF 病毒处理的肿瘤中中性粒细胞和巨噬细胞的浸润增加。这些发现有助于阐明正在进行临床试验的 GMCSF 武装痘苗病毒的作用机制。
