A new oncolytic Vaccinia virus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery
A new oncolytic Vaccinia virus augments antitumor immune responses to prevent tumor recurrence and metastasis after surgery
复制标题
一种新的溶瘤牛痘病毒增强抗肿瘤免疫反应，防止手术后肿瘤复发和转移
DOI：
10.1136/jitc-2019-000415
复制
发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Wang, Yaohe
中科院分区：
文献类型：
--
作者：
Ahmed, Jahangir;Chard, Louisa S.;Wang, Yaohe
背景局部复发和远处转移是提高肿瘤患者术后生存率的主要挑战。溶瘤病毒是预防术后疾病的特别有吸引力的选择，因为它们提供了一种无毒的治疗选择，可以直接靶向残留的肿瘤沉积物，并有益地调节术后被抑制的全身免疫环境，并允许残留疾病脱离控制。在这里，我们报告了一种新型的牛痘病毒（VV），VVΔTKΔ N1 L（缺失胸苷激酶（TK）和N1 L基因）武装与白细胞介素12（IL-12），可以延长术后生存期时，作为新辅助治疗在不同的小鼠和仓鼠手术模型的癌症。方法构建了一株肿瘤靶向性复制型VV-ΔTKΔ N1 L。这种病毒用IL-12合理武装。在几种临床相关模型中评估了VVΔTKΔ N1 L和VVΔTKΔ N1 L-IL 12对肿瘤微环境调节和肿瘤特异性免疫诱导的作用，以及作为预防术后复发和转移的新辅助剂的可行性和安全性。结果VVΔTKΔ N1 L作为新辅助治疗，可显著延长3种不同手术诱导的肿瘤转移模型的术后生存期。疗效严重依赖于循环自然杀伤细胞的增加，这是通过病毒诱导的细胞因子从N1 L缺失但N1 L完整VV感染的细胞中产生来实现的。通过用IL-12（一种强效抗肿瘤细胞因子）武装VVΔTKΔ N1 L，进一步增强了这种作用。术前VVΔTKΔ N1 L-IL 12每日5次治疗显著改善了术后生存率。在叙利亚仓鼠头颈癌手术模型中，VVΔTKΔ N1 L与人IL-12联合可完全预防肿瘤复发。结论这些数据为将该方案转化为临床试验提供了概念证明。VVΔTKΔ N1 L-IL 12是一种很有前途的药物，可用作实体瘤手术治疗的辅助剂。
Background Local recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novel Vaccinia virus (VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer. Methods A tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models. Results VVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters. Conclusions These data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.