Baker Alexander T, Aguirre-Hernández Carmen, Halldén Gunnel, Parker Alan L
Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
Cancers (Basel). 2018 Jun 14;10(6):201. doi: 10.3390/cancers10060201.
The licensing of talimogene laherparepvec (T-Vec) represented a landmark moment for oncolytic virotherapy, since it provided unequivocal evidence for the long-touted potential of genetically modified replicating viruses as anti-cancer agents. Whilst T-Vec is promising as a locally delivered virotherapy, especially in combination with immune-checkpoint inhibitors, the quest continues for a virus capable of specific tumour cell killing via systemic administration. One candidate is oncolytic adenovirus (Ad); it’s double stranded DNA genome is easily manipulated and a wide range of strategies and technologies have been employed to empower the vector with improved pharmacokinetics and tumour targeting ability. As well characterised clinical and experimental agents, we have detailed knowledge of adenoviruses’ mechanisms of pathogenicity, supported by detailed virological studies and in vivo interactions. In this review we highlight the strides made in the engineering of bespoke adenoviral vectors to specifically infect, replicate within, and destroy tumour cells. We discuss how mutations in genes regulating adenoviral replication after cell entry can be used to restrict replication to the tumour, and summarise how detailed knowledge of viral capsid interactions enable rational modification to eliminate native tropisms, and simultaneously promote active uptake by cancerous tissues. We argue that these designer-viruses, exploiting the viruses natural mechanisms and regulated at every level of replication, represent the ideal platforms for local overexpression of therapeutic transgenes such as immunomodulatory agents. Where T-Vec has paved the way, Ad-based vectors now follow. The era of designer oncolytic virotherapies looks decidedly as though it will soon become a reality.
talimogene laherparepvec（T-Vec）的获批是溶瘤病毒疗法的一个里程碑时刻，因为它为长期以来人们所鼓吹的经基因改造的复制型病毒作为抗癌药物的潜力提供了明确证据。虽然T-Vec作为一种局部递送的病毒疗法很有前景，尤其是与免疫检查点抑制剂联合使用时，但人们仍在继续寻找一种能够通过全身给药特异性杀死肿瘤细胞的病毒。一种候选病毒是溶瘤腺病毒（Ad）；其双链DNA基因组易于操作，并且已经采用了广泛的策略和技术来增强该载体的药代动力学和肿瘤靶向能力。作为特征明确的临床和实验药物，我们对腺病毒的致病机制有详细的了解，详细的病毒学研究和体内相互作用为其提供了支持。在这篇综述中，我们重点介绍了在定制腺病毒载体工程方面所取得的进展，这些载体能够特异性感染、在肿瘤细胞内复制并破坏肿瘤细胞。我们讨论了如何利用细胞进入后调节腺病毒复制的基因突变将复制限制在肿瘤内，并总结了对病毒衣壳相互作用的详细了解如何能够进行合理修饰以消除天然嗜性，同时促进癌组织的主动摄取。我们认为，这些利用病毒自然机制并在复制的各个层面进行调控的设计病毒，是局部过表达免疫调节剂等治疗性转基因的理想平台。T-Vec已经铺就了道路，基于Ad的载体现在紧随其后。溶瘤病毒疗法的设计时代似乎肯定很快就会成为现实。
