Introduction

Immunotherapy is a rapidly evolving area of cancer therapeutics aimed at driving a systemic immune response to fight cancer. Oncolytic viruses (OVs) are at the cutting-edge of innovation in the immunotherapy field. Successful OV platforms must be effective in reshaping the tumor microenvironment and controlling tumor burden, but also be highly specific to avoid off-target side effects. Large DNA viruses, like vaccinia virus (VACV), have a large coding capacity, enabling the encoding of multiple immunostimulatory transgenes to reshape the tumor immune microenvironment. VACV-based OVs have shown promising results in both pre-clinical and clinical studies, including safe and efficient intravenous delivery to metastatic tumors.

Area covered

This review summarizes attenuation strategies to generate a recombinant VACV with optimal tumor selectivity and immunogenicity. In addition, we discuss immunomodulatory transgenes that have been introduced into VACV and summarize their effectiveness in controlling tumor burden.

Expert opinion

VACV encodes several immunomodulatory genes which aid the virus in overcoming innate and adaptive immune responses. Strategic deletion of these virulence factors will enable an optimal balance between viral persistence and immunogenicity, robust tumor-specific expression of payloads and promotion of a systemic anti-cancer immune response. Rational selection of therapeutic transgenes will maximize the efficacy of OVs and their synergy in combinatorial immunotherapy schemes.

中文翻译：

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将牛痘病毒工程化为克服肿瘤异质性的免疫治疗战舰。

介绍

免疫疗法是癌症疗法的快速发展领域，旨在推动全身性免疫应答来对抗癌症。溶瘤病毒（OVs）处于免疫治疗领域的创新前沿。成功的OV平台必须有效地重塑肿瘤微环境并控制肿瘤负担，而且必须高度特异性，以避免脱靶副作用。大型DNA病毒（如痘苗病毒（VACV））具有较大的编码能力，可以编码多个免疫刺激性转基因，从而重塑肿瘤的免疫微环境。在临床前和临床研究中，基于VACV的OVs均显示出令人鼓舞的结果，包括安全，有效地将静脉内转移至转移性肿瘤。

覆盖面积

这篇综述总结了产生具有最佳肿瘤选择性和免疫原性的重组VACV的减毒策略。此外，我们讨论了已被引入VACV的免疫调节转基因，并总结了其在控制肿瘤负荷方面的有效性。

专家意见

VACV编码几种免疫调节基因，这些基因可帮助病毒克服先天性和适应性免疫应答。这些毒力因子的战略性删除将使病毒的持久性和免疫原性，有效负载的强大的肿瘤特异性表达和促进全身性抗癌免疫反应之间达到最佳平衡。合理选择治疗性转基因将使OVs的功效及其在组合免疫治疗方案中的协同作用最大化。