Developing Species D adenovirus vectors for cancer applications

Bates, Emily 2022. Developing Species D adenovirus vectors for cancer applications. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Oncolytic viruses harness the natural ability of viruses to infect cells causing cells lysis and stimulation of the immune system, making them intriguing platforms for novel tumour specific cancer therapies. Oncolytic adenoviral therapies are excellent candidates with a readily modifiable double stranded DNA genome and proven safety profile. HAdV-C5 is a common choice for clinical and experimental application applications, however off-target interactions and high levels of pre-existing immunity against Ad5 warrant investigation into alternative serotypes. Species D, the largest of the adenoviral species, offer significant potential as they are less common and consequently have low levels of pre-existing immunity in the population. The hypothesis of this is that Species D adenoviral serotypes have potential as oncolytic virotherapy vectors. Species D, HAdV-D10 has advantages over HAdV-C5 based therapies with weaker native receptor interactions, lack of interaction with FX which can cause uptake in the liver and low seroprevalence. HAdV-D10 was vectorised and rendered replication deficient through removal of E1 and E3 genes. Replacement of E4orf6 with that from HAdV-C5 aided production in 293 cells, and reporter genes were inserted in E1. The HAdV-D10 vector was targeted to αvβ6 integrin expressing epithelial cancers such as pancreatic, breast and oesophageal through insertion of the A20 peptide into the DG loop of the fiber knob. Similarly, HAdV-D10 was targeted to glioma through incorporation of RGD4C which targets αvβ3 and αvβ5. Through engineering the fiber knob protein, HAdV-D10 was developed into a highly selective, targeted virotherapy. HAdV-D10 targeted vectors can be further improved through incorporation of transgenes, such as immunotherapies, to improve potency and efficacy. An alternative approach was to “evolve” tumour selective recombinants through natural recombination of pooled wild-type HAdV-D serotypes on oesophageal cancer cell line, Kyse 30. Lead recombinants were isolated and sequenced to determine the parental chimera. This research highlights the importance of species D as oncolytic adenoviral therapies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	20 March 2023
Last Modified:	20 Mar 2023 14:56
URI:	https://orca.cardiff.ac.uk/id/eprint/157825

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