Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Department of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.01386-18. Print 2018 Dec 1.
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virus (NDV), named recombinant VSV-NDV (rVSV-NDV), wherein the VSV backbone is conserved but its glycoprotein has been replaced by the hemagglutinin-neuraminidase (HN) and the modified, hyperfusogenic fusion (F) envelope proteins of recombinant NDV.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-to-cell 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-prkdc/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 immune-competent 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. 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.
溶瘤病毒代表了癌症免疫治疗这一不断发展领域的一个令人兴奋的新方面。我们构建了一种新型的混合载体，由水疱性口炎病毒（VSV）和新城疫病毒（NDV）组成，命名为重组 VSV-NDV（rVSV-NDV），其中 VSV 骨架得以保留，但糖蛋白已被重组 NDV 的血凝素神经氨酸酶（HN）和修饰的、高融合性融合（F）包膜蛋白所取代。与通过典型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，从而实现病毒的高效细胞间传播和免疫原性细胞死亡的快速发生。此外，糖蛋白交换大大消除了与野生型 VSV 相关的脑和肝组织中的脱靶效应，导致安全性显著提高，甚至在对野生型 VSV 高度易感的免疫缺陷 NOD.CB17-prkdc/NCrCrl（NOD-SCID）小鼠中也是如此。尽管 NDV 在其自然禽类宿主中引起严重的致病性，但在嵌合 rVSV-NDV 载体中加入包膜蛋白后，该病毒在鸡胚卵中是无毒的。最后，在具有免疫能力的原位肝癌（HCC）荷瘤小鼠中进行 rVSV-NDV 的全身给药导致显著的生存延长。因此，该策略将快速复制的 VSV 平台的有益特性与高效传播和免疫原性细胞死亡的融合病毒相结合，而不会带来与任何亲本载体相关的安全性和环境威胁。综合这些数据，rVSV-NDV 作为一种安全有效的溶瘤病毒，代表了一种有吸引力的临床转化载体平台。溶瘤病毒治疗的疗效常常需要在安全性方面做出权衡，因此，有效的载体往往与毒性相关，而更安全的病毒则往往具有减弱的治疗效果。尽管有很有前景的临床前数据，但 VSV 作为一种临床制剂的发展受到了严重阻碍，因为野生型 VSV 治疗会导致啮齿动物和非人灵长类动物出现严重的神经毒性和肝毒性。尽管 NDV 在人类中具有吸引人的安全性特征，并具有有前景的溶瘤作用，但由于它所带来的环境风险，其进一步发展受到了严重限制。因此，杂交 rVSV-NDV 载体是一种极具前途的载体平台，因为它在对受者和环境均安全的同时，同时通过直接溶瘤作用和诱导免疫原性细胞死亡来发挥作用，因此是有效的。
