Development of adenovirus- and cytomegalovirus-based viral vectors expressing 5T4 in cancer vaccination strategies

Williams, Marta 2022. Development of adenovirus- and cytomegalovirus-based viral vectors expressing 5T4 in cancer vaccination strategies. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Anti-cancer vaccines, mobilising immunotherapeutic strategies to both prevent and kill cancer cells, have recently regained significant interest as exciting therapeutic modalities. The prevailing immunisation strategy with antigenbased cancer vaccines utilises tumour-associated antigens as therapeutic targets. These antigens, over-expressed on tumour cells and hardly present on normal tissues, are shared by various tumours and allow for universal application. This thesis explores immunogenicity of several murine cytomegalovirus- and adenovirus-based viral vectors expressing tumour-associated antigen 5T4, and their potential as prophylactic viral vaccines in a murine model of colorectal cancer. I first optimised an inducible mouse model of colorectal cancer, which allows for a controlled deletion of gatekeeper Apc gene in intestinal stem cells, mirroring events at the early stages of most sporadic colorectal cancers. This leads to the formation of microadenomas in intestinal crypts, and their quantification can be used to assess protective efficacy of viral vaccines. Immunisations with whole length 5T4 failed to induce powerful CD8+ T cellbased responses, both with MCMV- and adenovirus-based vectors, including Ad vectors with altered tropism, pseudotyped with less common serotype proteins. However, immunisation with Ad5 vectors expressing individual epitopes from the 5T4 antigen induced large expansions of polyfunctional 5T4- specific T-cell responses. In contrast to classical epitope-specific effector iii memory T-cell populations, these vaccine-induced T-cell responses were maintained over time and lacked features of T cell exhaustion. Ad5 vector expressing 5T4 inflationary epitope VSFRNLTHL with a HCMVderived signal peptide UL40 showed further immunogenicity enhancement. Vaccine-induced T-cell responses promoted anti-tumour protection in a mouse model of colorectal cancer that endogenously expressed 5T4, with a suppressed microadenoma growth in mice. Overall, this thesis demonstrates the ability to modify adenoviral-based vectors expressing 5T4 inflationary epitope with HCMV derived signal peptide UL40 to induce protective antitumour T-cell responses against tumour-associated antigen and implies the exciting potential of exploiting these approaches in cancer vaccination strategies in the future.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	12 May 2023
Last Modified:	12 May 2023 09:33
URI:	https://orca.cardiff.ac.uk/id/eprint/159424

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