Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus
Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus
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DOI：
10.1038/sj.cgt.7701070
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发表时间：
2007-11-01
影响因子：
6.4
通讯作者：
Nishiyama, Y.
中科院分区：
文献类型：
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作者：
Kohno, S-i;Luo, C.;Nishiyama, Y.
实体瘤的直接病毒感染可导致肿瘤细胞死亡，但这些技术提供了表达外源因子以增强抗肿瘤反应的机会。我们研究了单纯疱疹病毒（HSV）扩增子表达小鼠粒细胞-巨噬细胞集落刺激因子（mGM-CSF）的抗肿瘤作用，使用具有复制能力的HSV 1型突变体HF 10作为辅助病毒。使用HF 10包装的表达mGM-CSF的扩增子（mGM-CSF扩增子）感染皮下接种的鼠结肠直肠肿瘤细胞（CT 26细胞），并将抗肿瘤效果与仅用HF 10处理的肿瘤进行比较。mGM-CSF扩增子在CT 26细胞中有效复制，具有与HF 10相似的体外溶瘤活性。然而，当皮下接种CT 26细胞的小鼠瘤内注射HF 10或mGM-CSF扩增子时，在mGM-CSF扩增子处理的动物中观察到更大的肿瘤消退。此外，mGM-CSF扩增子治疗延长了小鼠的生存期。免疫组织化学分析显示，在mGM-CSF扩增子处理的动物中，实体瘤中的炎性细胞浸润增加。这些结果表明，GM-CSF的表达增强了HF 10的抗肿瘤作用，并且HF 10包装的表达GM-CSF的扩增子是用于治疗皮下肿瘤的有希望的药剂。
Direct viral infection of solid tumors can cause tumor cell death, but these techniques offer the opportunity to express exogenous factors to enhance the antitumor response. We investigated the antitumor effects of a herpes simplex virus (HSV) amplicon expressing mouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) using the replication-competent HSV type 1 mutant HF10 as a helper virus. HF10-packaged mGM-CSF-expressing amplicon (mGM-CSF amplicon) was used to infect subcutaneously inoculated murine colorectal tumor cells (CT26 cells) and the antitumor effects were compared to tumors treated with only HF10. The mGM-CSF amplicon efficiently replicated in CT26 cells with similar oncolytic activity to HF10 in vitro. However, when mice subcutaneously inoculated with CT26 cells were intratumorally injected with HF10 or mGM-CSF amplicon, greater tumor regression was seen in mGM-CSF amplicon-treated animals. Furthermore, mGM-CSF amplicon treatment prolonged mouse survival. Immunohistochemical analysis revealed increased inflammatory cell infiltration in the solid tumor in the mGM-CSF amplicon-treated animals. These results suggest that expression of GM-CSF enhances the antitumor effects of HF10, and HF10-packaged GM-CSF-expressing amplicon is a promising agent for the treatment of subcutaneous tumors.