Designer Oncolytic Adenovirus: Coming of Age.
Designer Oncolytic Adenovirus: Coming of Age.
复制标题
DOI：
10.3390/cancers10060201
复制
发表时间：
2018-06-14
期刊：
影响因子：
5.2
通讯作者：
Parker AL
中科院分区：
文献类型：
--
作者：
Baker AT;Aguirre-Hernández C;Halldén G;Parker AL
talimogene laherparepvec (T-Vec) 的许可代表了溶瘤病毒疗法的里程碑时刻，因为它为长期以来吹捧的转基因复制病毒作为抗癌药物的潜力提供了明确的证据。虽然 T-Vec 作为一种局部递送的病毒疗法很有前景，特别是与免疫检查点抑制剂联合使用，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。一种候选者是溶瘤腺病毒（Ad）；它的双链DNA基因组易于操作，并且采用了广泛的策略和技术来赋予载体改善的药代动力学和肿瘤靶向能力。作为经过充分表征的临床和实验药物，我们对腺病毒的致病机制有详细的了解，并得到详细的病毒学研究和体内相互作用的支持。在这篇综述中，我们重点介绍了定制腺病毒载体工程在特异性感染、在肿瘤细胞内复制和破坏肿瘤细胞方面取得的进展。我们讨论了如何利用进入细胞后调节腺病毒复制的基因突变来限制复制到肿瘤，并总结了病毒衣壳相互作用的详细知识如何能够进行合理修饰以消除天然趋向性，同时促进癌组织的主动摄取。我们认为，这些设计病毒利用病毒的自然机制并在各个复制水平上进行调节，代表了治疗性转基因（例如免疫调节剂）局部过度表达的理想平台。 T-Vec 已经铺平了道路，基于 Ad 的载体现在也紧随其后。设计溶瘤病毒疗法的时代看起来很快就会成为现实。
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.
登录
查看更多内容
影响因子：
6.2
作者：
Aguirre-Hernandez, Carmen;Maya-Pineda, Hector;Hallden, Gunnel
通讯作者：
Hallden, Gunnel
影响因子：
11.5
作者：
Allen, Michael D.;Thomas, Gareth J.;Jones, J. Louise
通讯作者：
Jones, J. Louise
影响因子：
5.4
作者：
Banerjee, Partha Sarathi;Ostapchuk, Philomena;Carrico, Isaac Sheridan
通讯作者：
Carrico, Isaac Sheridan
影响因子：
5.4
作者：
Belousova, N;Krendelchtchikova, V;Krasnykh, V
通讯作者：
Krasnykh, V
影响因子：
5.1
作者：
Alemany, R;Curiel, DT
通讯作者：
Curiel, DT