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 (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.
Highlights
Once described by Peter Medawar as “a piece of bad news wrapped up in protein” [1], oncolytic viruses are beginning to emerge as clinically useful agents in the cancer arena
Once natural tropisms have been ablated, in order to generate a cancer targeted virotherapy, it is necessary to provide an alternative means of infecting the cell; one which is specific to the tissue of interest
An important benefit of the chimeric retargeting approach is highlighted in a study of a “knobless” adenovirus in which the fiber protein was engineered to have 7 shaft repeats, a trimerization motif, and the anti-Taq polymerase Ztaq affibody; this generated the Ad5/R7-Ztaq -Ztaq virus based on Ad5 [232]
Summary
Once described by Peter Medawar (recipient of the 1960 Nobel prize for the discovery of immunological tolerance) as “a piece of bad news wrapped up in protein” [1], oncolytic viruses are beginning to emerge as clinically useful agents in the cancer arena. Few virotherapies have seen as much development as those based on adenovirus (Ad) These non-enveloped, double stranded DNA viruses are generating increasing interest as therapeutic. Of Whether is designed a vaccine, therapy, gene therapy, virus, all dependent our ability to engineer thesemanipulate viruses and their or oncolytic virus, or alloncolytic are dependent onare our ability toonengineer these viruses and manipulate natural tropisms to ablate and achieve therapeutic benefit. Natural tropismstheir to ablate pathogenicity and pathogenicity achieve therapeutic benefit This engineering is based on intricate understanding of adenovirus virology. These nonThis engineering is based on intricate understanding of adenovirus virology Of adenoviral structure can be found in the review by Russell [6]
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