溶瘤呼肠孤病毒作为联合抗病毒和抗肿瘤剂用于肝癌的治疗

Adel Samson ,Matthew J Bentham,Karen Scott,Gerard Nuovo ,Abigail Bloy ,Elizabeth Appleton,Robert A Adair , Rajiv Dave,Adam Peckham-Cooper ,Giles Toogood , Seishi Nagamori ,Matthew Coffey , Richard Vile ,Kevin Harrington ,Peter Selby ,Fiona Errington-Mais ,Alan Melcher,Stephen Griffin

本刊负责人：窦晓光  中国医科大学附属盛京医院感染科　

审校：张缭云  山西医科大学第一医院感染病科 

翻译：魏荣荣  山西医科大学研究生 

摘要

目的 溶瘤病毒（oncolytic viruses , OVs）代表了前景广阔的促炎性癌症治疗方案。在此，我们探讨了OV 诱导的固有免疫反应是否可在抑制肝细胞癌（hepatocellularcarcinoma , HCC）的同时抑制HCV。此外，我们将这个范例推广至其他病毒相关癌症模型的研究。

设计与结果 临床级别的溶瘤呼肠孤病毒（reovirus , Reo）可在无细胞毒性以及不依赖病毒基因组复制的情况下，激活原代人肝组织内的固有免疫系统。Reo 诱导的细胞因子应答不仅在体外和体内能有效抑制HCV 复制，而且在HCC 的临床前模型中通过激活固有的去颗粒化免疫细胞获得疗效。此外，Reo 诱导的固有免疫应答，对HBV 相关的HCC 模型以及EB 病毒相关淋巴瘤的另一种内源性模型同样有效。有趣的是，Reo 从原发性肝组织诱发固有炎性应答的能力似乎优于大多数OVs。

结论 我们建议：Reo 及其他优选的促炎性OV 可用于治疗与致癌病毒感染相关的多种癌症，同时减少病毒相关的致癌驱动基因和肿瘤负荷。对于HCV 相关的HCC（HCV-HCC）， 应将Reo 视为补充和支持目前HCVHCC治疗方案的替代选择，特别是在那些新型HCV 抗病毒疗法的使用可能受限的国家。

Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer

Adel Samson ,Matthew J Bentham,Karen Scott ,Gerard Nuovo ,Abigail Bloy ,Elizabeth Appleton,Robert A Adair , Rajiv Dave,Adam Peckham-Cooper ,Giles Toogood , Seishi Nagamori ,Matthew Coffey , Richard Vile ,Kevin Harrington ,Peter Selby ,Fiona Errington-Mais ,Alan Melcher,Stephen Griffin

ABSTRACT

Objective  Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virusassociated cancer.

Design and results Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBVassociated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. 

Conclusions We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCVassociated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited.

Gut Mar 2018, 67 (3) 562-573; DOI: 10.1136/gutjnl-2016-312009

https://gut.bmj.com/content/67/3/562

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