Preprint Review Version 1 This version is not peer-reviewed

Designer Oncolytic Adenovirus: Coming of Age

Version 1 : Received: 20 May 2018 / Approved: 21 May 2018 / Online: 21 May 2018 (12:27:56 CEST)
Version 2 : Received: 14 June 2018 / Approved: 15 June 2018 / Online: 15 June 2018 (05:14:24 CEST)

A peer-reviewed article of this Preprint also exists.

Baker, A.T.; Aguirre-Hernández, C.; Halldén, G.; Parker, A.L. Designer Oncolytic Adenovirus: Coming of Age. Cancers 2018, 10, 201. Baker, A.T.; Aguirre-Hernández, C.; Halldén, G.; Parker, A.L. Designer Oncolytic Adenovirus: Coming of Age. Cancers 2018, 10, 201.

Journal reference: Cancers 2018, 10, 201
DOI: 10.3390/cancers10060201

Abstract

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; 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.

Subject Areas

adenovirus; oncolytic; targeting; virotherapy; cancer; αvβ6 integrin; immunotherapy; tropism

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