Authors' Affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Cancer Immunol Res. 2013 Nov;1(5):309-19. doi: 10.1158/2326-6066.CIR-13-0059-T. Epub 2013 Aug 19.
Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death-inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8(+) T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens.
尽管单纯疱疹病毒 1（HSV-1）ICP0 缺失溶瘤载体在鼠乳腺癌模型中的抗肿瘤活性已得到验证，但单纯的溶瘤病毒治疗不足以打破免疫耐受。因此，我们研究了通过与免疫原性细胞死亡诱导化疗药物米托蒽醌联合治疗来增强疗效。尽管体外缺乏增强的细胞毒性，但用 5 μmol/L 米托蒽醌处理 HSV-1 ICP0 缺失溶瘤病毒 KM100 可使携带 Her2/neu TUBO 衍生肿瘤的 BALB/c 小鼠显著延长生存时间。这种保护作用是通过增加肿瘤内中性粒细胞和肿瘤抗原特异性 CD8+T 细胞的浸润来介导的。耗竭研究证实，CD8+、CD4+和 Ly6G 表达细胞是联合治疗增强疗效所必需的。此外，米托蒽醌联合 KM100 溶瘤病毒治疗可打破携带 TUBO 衍生肿瘤的 BALB-neuT 小鼠的免疫耐受。本研究表明，溶瘤病毒联合免疫原性细胞死亡诱导化疗药物可增强肿瘤相关抗原的免疫原性，打破针对这些抗原建立的免疫耐受。
