Novel strategies for developing tumour selective virotherapies

Swift, Emma 2025. Novel strategies for developing tumour selective virotherapies. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Oncolytic virotherapy is a promising, emerging cancer treatment strategy that seeks to harness the cytolytic and immunostimulatory properties of viruses for therapeutic benefit by selectively targeting these activities towards malignant cells. Viruses contained within the Adenoviridae family are especially appealing candidates from which to construct virotherapy vectors. Nonetheless, the broad native tropisms of naturally occurring adenoviral types pose a challenge to the safety and efficacy of therapeutics based on these backbones. This thesis aimed to examine strategies for modifying adenoviral capsids to generate precision-targeted, tumour cell entry selective cancer therapy vectors. We have demonstrated that adenoviral fiber knob proteins derived from low seroprevalence species B and D viruses can be targeted to the cancer-associated αvβ6 integrin by a combination of A20 peptide insertion and native tropism ablating mutations. Ad5-based vectors pseudotyped with these domains selectively transduced αvβ6-expressing cells in vitro, whilst partially evading neutralisation by anti-Ad5 human plasma. We further investigated the potential of several αvβ6-targeted agents to act as positron emission tomography (PET) tracers. Streptavidin-biotin-PEG6-A20-PEG6 and a monoclonal anti-αvβ6 antibody (620W.7) selectively accumulated in αvβ6-expressing murine xenografts, whereas a recombinant αvβ6-binding adenoviral fiber knob protein did not. Finally, we evaluated genetic and non-genetic approaches through which to generate adenovirotherapy vectors targeted towards alternative tumour-associated antigens. Heterologous peptide inserts designed to bind fibroblast growth factor receptor 2b were not successful in redirecting virus cell entry. However, we have developed a platform for the stable, site-specific coupling of tropism�modifying adaptors to an Ad5 vector by employing the spontaneously reacting DogTag and DogCatcher peptide/protein pair.These findings highlight the feasibility of generating cell entry selective adenoviral therapy vectors. Such platforms are optimally poised to treat cancers expressing a range of tumour-associated antigens, whilst minimally impacting healthy bystander tissues.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	5 November 2025
Last Modified:	05 Nov 2025 10:28
URI:	https://orca.cardiff.ac.uk/id/eprint/182107

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