Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapeutics, School of Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapeutics, School of Medicine, Tottori University Faculty of Medicine, 86 Nishi-cho, Yonago 683-8503, Japan.
Mol Ther. 2021 May 5;29(5):1782-1793. doi: 10.1016/j.ymthe.2020.12.024. Epub 2020 Dec 19.
Oncolytic viruses induce antitumor immunity following direct viral oncolysis. However, their therapeutic effects are limited in distant untreated tumors because their antitumor function depends on indirect antitumor immunity. Here, we generated a novel fusogenic oncolytic vaccinia virus (FUVAC) and compared its antitumor activity with that of its parental non-fusogenic virus. Compared with the parent, FUVAC exerted the cytopathic effect and induced immunogenic cell death in human and murine cancer cells more efficiently. In a bilateral tumor-bearing syngeneic mouse model, FUVAC administration significantly inhibited tumor growth in both treated and untreated tumors. However, its antitumor effects were completely suppressed by CD8 T cell depletion. Notably, FUVAC reduced the number of tumor-associated immune-suppressive cells in treated tumors, but not in untreated tumors. Mice treated with FUVAC before an immune checkpoint inhibitor (ICI) treatment achieved complete response (CR) in both treated and untreated tumors, whereas ICI alone did not show antitumor activity. Mice achieving CR rejected rechallenge with the same tumor cells, suggesting establishment of a long-term tumor-specific immune memory. Thus, FUVAC improves the tumor immune microenvironment and enhances systemic antitumor immunity, suggesting that, alone and in combination with ICI, it is a novel immune modulator for overcoming oncolytic virus-resistant tumors.
溶瘤病毒通过直接病毒溶瘤诱导抗肿瘤免疫。然而，由于其抗肿瘤功能取决于间接抗肿瘤免疫，因此它们在未治疗的远处肿瘤中的治疗效果有限。在这里，我们生成了一种新型融合溶瘤痘苗病毒（FUVAC），并比较了其与亲本非融合病毒的抗肿瘤活性。与亲本相比，FUVAC 更有效地在人和鼠癌细胞中发挥细胞病变作用并诱导免疫原性细胞死亡。在双侧荷瘤同种小鼠模型中，FUVAC 给药显著抑制了治疗和未治疗肿瘤的肿瘤生长。然而，其抗肿瘤作用完全被 CD8 T 细胞耗竭所抑制。值得注意的是，FUVAC 减少了治疗肿瘤中肿瘤相关免疫抑制细胞的数量，但未减少未治疗肿瘤中的数量。在用免疫检查点抑制剂（ICI）治疗之前用 FUVAC 治疗的小鼠在治疗和未治疗的肿瘤中均达到完全缓解（CR），而 ICI 单独治疗则没有抗肿瘤活性。获得 CR 的小鼠排斥相同肿瘤细胞的再挑战，表明建立了长期的肿瘤特异性免疫记忆。因此，FUVAC 改善了肿瘤免疫微环境并增强了全身抗肿瘤免疫，表明它是一种单独使用和与 ICI 联合使用的新型免疫调节剂，可克服溶瘤病毒耐药肿瘤。
