Development of precision virotherapies capable of evading neutralising anti-vector immunity

Wallace, Rebecca 2024. Development of precision virotherapies capable of evading neutralising anti-vector immunity. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Adenoviruses, particularly Ad5, are commonly investigated as potent oncolytic agents. They can be made conditionally replicating, decreasing the risk of damage to healthy tissues. Oncolytic cell death will activate the immune system and allow for the initiation of an antitumour immune response. Furthermore, a variety of transgenes can be encoded to aid oncolytic activity. The previously generated Ad5NULLA20 vector has shown great promise, as it is highly tumour selective through insertion of the A20 peptide. This modified vector is effectively retargeted to tumours high in αvβ6 integrin both in vitro and in vivo after intravenous administration in mice, while ablating all native receptor binding. However, for maximum effect oncolytic viruses should be administered systemically to target early metastatic sites along with the primary tumour. If vectors encounter pre-existing immunity to adenoviruses in the form of neutralising antibodies, this may greatly reduce their effect as a cancer therapeutic. In this thesis, several different strategies were explored to increase Ad vector evasion of neutralising immunity. Rare serotype species D Ads were assessed for their suitability as oncolytics. Their genome capture into an in-house vectorisation system was attempted. Whole and partial hexon swaps with rare species D Ads, as well as partial hexon deletions, were attempted and resulting vectors were evaluated for their evasion of neutralising antibodies in vitro. Additionally, genetic-chemical shielding approaches of Ad5 based vectors were explored. Whilst whole serotype genome capture was unsuccessful, important information on the infective pattern of selected species D Ads was acquired. Whole hexon swaps proved structurally incompatible, however exchanges in hypervariable regions (HVRs) 5 and 7 were more successful. Resulting vectors showed only limited improvement on immune evasion. HVR1 deletions presented surprising evasion of innate immune factors, as transduction by Ad5dHVR1 was only reduced by 5%, while Ad5 transduction was reduced by 75% in vitro in unvaccinated mouse serum, indicating future research would be beneficial. Chemical shielding approaches were optimised and could be vastly beneficial to quickly and effectively shield vectors with a variety of novel polymers.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Funders:	Cancer Research UK
Date of First Compliant Deposit:	6 February 2025
Last Modified:	10 Feb 2025 13:19
URI:	https://orca.cardiff.ac.uk/id/eprint/175997

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