University of Pittsburgh Cancer Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mol Cancer. 2013 Sep 11;12(1):103. doi: 10.1186/1476-4598-12-103.
Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.
溶瘤病毒（OVs）是一种肿瘤选择性、多机制的抗肿瘤药物。它们通过直接溶瘤作用杀死受感染的癌症和相关的内皮细胞，通过肿瘤血管靶向和旁观者效应杀死未受感染的细胞。OVs 诱导的多模式免疫原性细胞死亡（ICD）和自噬通常不仅向树突状细胞呈现强烈的危险信号，而且还能有效地将肿瘤相关抗原从癌细胞交叉呈递给树突状细胞和 T 细胞，从而诱导适应性抗肿瘤免疫。在这种有利的免疫背景下，对 OVs 进行基因工程和合理组合进一步增强了 OVs 作为癌症疫苗的作用。携带 GM-CSF（如 T-VEC 和 Pexa-Vec）或其他免疫刺激基因的 OVs，在动物模型和人类患者中均能诱导强烈的抗肿瘤免疫。与其他免疫治疗方案联合使用可提高整体治疗效果。与组蛋白去乙酰化酶抑制剂联合使用可短暂抑制固有免疫，促进 OVs 的感染和传播，显著增强抗肿瘤免疫并提高治疗指数。局部给药或 OV 介导表达 Toll 样受体配体可以挽救肿瘤浸润 CD8+T 细胞被免疫抑制性肿瘤微环境抑制的功能，从而增强抗肿瘤作用。与环磷酰胺联合使用可进一步诱导 ICD，耗竭 Treg，从而增强抗肿瘤免疫。总之，经过适当武装或合理组合的 OVs 是有效的治疗性癌症疫苗。
