A Novel Chimeric Oncolytic Virus Vector for Improved Safety and Efficacy as a Platform for the Treatment of Hepatocellular Carcinoma
A Novel Chimeric Oncolytic Virus Vector for Improved Safety and Efficacy as a Platform for the Treatment of Hepatocellular Carcinoma
复制标题
DOI：
10.1128/jvi.01386-18
复制
发表时间：
2018-12-01
影响因子：
5.4
通讯作者：
Altomonte, Jennifer
中科院分区：
文献类型：
--
作者：
Abdullahi, Sarah;Jaekel, Melanie;Altomonte, Jennifer
溶瘤病毒代表了癌症免疫治疗领域不断发展的一个令人兴奋的新方面。我们设计了一种新的包含水泡性口炎病毒（VSV）和纽卡斯尔病病毒（NDV）的杂合载体，命名为重组VSV-NDV（rVSV-NDV），其中VSV骨架是保守的，但其糖蛋白已被重组NDV的血凝素-神经氨酸酶（HN）和经修饰的超致流融合（F）包膜蛋白取代。与通过经典的致细胞病变效应杀死细胞的野生型VSV相比，重组病毒能够诱导肿瘤特异性合胞体形成，允许病毒的有效细胞间传播和免疫原性细胞死亡的快速发生。此外，糖蛋白交换基本上消除了与野生型VSV相关的脑和肝组织中的脱靶效应，从而显着增强了安全性，即使在免疫缺陷NOD.CB17-prkdoc'd/NCrCrl（NOD-SCID）小鼠中也是如此，这些小鼠对野生型VSV高度敏感。虽然NDV在其天然禽类宿主中引起严重的致病性，但在嵌合rVSV-NDV载体中掺入包膜蛋白在含胚鸡蛋中是无毒的。最后，rVSV-NDV在原位肝细胞癌（HCC）免疫小鼠中的全身给药导致显著的存活延长。因此，该策略将快速复制的VSV平台的有益特性与融合病毒的高效传播和免疫原性细胞死亡相结合，而没有与任一亲本载体相关的安全性和环境威胁的风险。将这些数据放在一起，rVSV-NDV代表了一个有吸引力的载体平台，用于临床翻译为一种安全有效的溶瘤病毒。重要性溶瘤病毒治疗的治疗效果往往是与安全性的权衡，这样，有效的载体往往与毒性有关，而更安全的病毒往往具有减弱的治疗效果。尽管有前景的临床前数据，VSV作为一种临床药物的发展已大大阻碍了这一事实，即严重的神经毒性和肝毒性已观察到在啮齿动物和非人灵长类动物中响应野生型VSV治疗。虽然NDV已被证明在人类中具有有吸引力的安全性，并具有有希望的溶瘤作用，但由于其造成的环境风险，其进一步发展受到严重限制。因此，杂合rVSV-NDV载体代表了一种非常有前途的载体平台，因为它已经被合理地设计为对受体和环境都是安全的，同时通过其直接溶瘤作用和通过诱导免疫原性细胞死亡都是有效的。
Oncolytic viruses represent an exciting new aspect of the evolving field of cancer immunotherapy. We have engineered a novel hybrid vector comprising vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV), named recombinant VSV-NDV (rVSV-NDV), wherein the VSV backbone is conserved but its glycoprotein has been replaced by the hemagglutinin-neuraminidase (HN) and the modified, hyperfusogenic fusion (F) envelope proteins of recombinant NDV. In comparison to wild-type VSV, which kills cells through a classical cytopathic effect, the recombinant virus is able to induce tumor-specific syncytium formation, allowing efficient cell-tocell spread of the virus and a rapid onset of immunogenic cell death. Furthermore, the glycoprotein exchange substantially abrogates the off-target effects in brain and liver tissue associated with wild-type VSV, resulting in a markedly enhanced safety profile, even in immune-deficient NOD.CB17-prkdoc'd/NCrCrl (NOD-SCID) mice, which are highly susceptible to wild-type VSV. Although NDV causes severe pathogenicity in its natural avian hosts, the incorporation of the envelope proteins in the chimeric rVSV-NDV vector is avirulent in embryonated chicken eggs. Finally, systemic administration of rVSV-NDV in orthotopic hepatocellular carcinoma (HCC)-bearing immunecompetent mice resulted in significant survival prolongation. This strategy, therefore, combines the beneficial properties of the rapidly replicating VSV platform with the highly efficient spread and immunogenic cell death of a fusogenic virus without risking the safety and environmental threats associated with either parental vector. Taking the data together, rVSV-NDV represents an attractive vector platform for clinical translation as a safe and effective oncolytic virus.IMPORTANCE The therapeutic efficacy of oncolytic viral therapy often comes as a tradeoff with safety, such that potent vectors are often associated with toxicity, while safer viruses tend to have attenuated therapeutic effects. Despite promising preclinical data, the development of VSV as a clinical agent has been substantially hampered by the fact that severe neurotoxicity and hepatotoxicity have been observed in rodents and nonhuman primates in response to treatment with wild-type VSV. Although NDV has been shown to have an attractive safety profile in humans and to have promising oncolytic effects, its further development has been severely restricted due to the environmental risks that it poses. The hybrid rVSV-NDV vector, therefore, represents an extremely promising vector platform in that it has been rationally designed to be safe, with respect to both the recipient and the environment, while being simultaneously effective, both through its direct oncolytic actions and through induction of immunogenic cell death.