Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Mol Ther. 2011 Feb;19(2):335-44. doi: 10.1038/mt.2010.264. Epub 2010 Nov 30.
Oncolytic virotherapy, the selective killing of tumor cells by oncolytic viruses (OVs), has emerged as a promising avenue of anticancer research. We have previously shown that KM100, a Herpes simplex virus type-1 (HSV) deficient for infected cell protein 0 (ICP0), possesses substantial oncolytic properties in vitro and has antitumor efficacy in vivo, in part by inducing antitumor immunity. Here, we illustrate through T-cell immunodepletion studies in nontolerized tumor-associated antigen models of breast cancer that KM100 treatment promotes antiviral and antitumor CD8(+) cytotoxic T-cell responses necessary for complete tumor regression. In tolerized tumor-associated antigen models of breast cancer, antiviral CD8(+) cytotoxic T-cell responses against infected tumor cells correlated with the induction of significant tumoristasis in the absence of tumor-associated antigen-specific CD8(+) cytotoxic T-cells. To enhance oncolysis, we tested a more cytopathic ICP0-null HSV and a vesicular stomatitis virus M protein mutant and found that despite improved in vitro replication, oncolysis in vivo did not improve. These studies illustrate that the in vitro cytolytic properties of OVs are poor prognostic indicators of in vivo antitumor activity, and underscore the importance of adaptive antiviral CD8(+) cytotoxic T-cells in effective cancer virotherapy.
溶瘤病毒治疗，即通过溶瘤病毒选择性杀伤肿瘤细胞，已成为癌症研究的一个很有前途的方向。我们之前的研究表明，缺失了感染细胞蛋白 0（ICP0）的单纯疱疹病毒 1 型（HSV-1）KM100 在体外具有很强的溶瘤特性，并具有体内抗肿瘤功效，其部分作用机制是诱导抗肿瘤免疫。在乳腺癌肿瘤相关抗原模型中，通过 T 细胞免疫耗竭研究，我们发现未经耐受的 KM100 治疗可促进抗病毒和抗肿瘤 CD8+细胞毒性 T 细胞反应，这是完全肿瘤消退所必需的。在乳腺癌肿瘤相关抗原耐受模型中，针对感染肿瘤细胞的抗病毒 CD8+细胞毒性 T 细胞反应与在缺乏肿瘤相关抗原特异性 CD8+细胞毒性 T 细胞的情况下诱导显著的肿瘤抑制相关。为了增强溶瘤作用，我们测试了一种更具细胞毒性的 ICP0 缺失 HSV 和一种水疱性口炎病毒 M 蛋白突变体，发现尽管体外复制能力得到了改善，但体内溶瘤作用并没有得到改善。这些研究表明，OV 的体外细胞溶解特性是体内抗肿瘤活性的不良预后指标，并强调了适应性抗病毒 CD8+细胞毒性 T 细胞在有效的癌症溶瘤治疗中的重要性。
