Development of novel immunotherapy: Virotherapy combinations for head and neck cancer

Moses, Elise 2024. Development of novel immunotherapy: Virotherapy combinations for head and neck cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Head and neck cancer (HNC) is the eighth most common cancer with an unmet clinical need for treatment of more aggressive cases. Limited success of therapies in drug discovery pipelines and in clinics has been aƩributed to a lack of models that closely resemble the tumour of origin. Tumour outgrowth is aided by escape of immune surveillance, thus the aim of translaƟonal cancer immunotherapy is to harness the power of the adapƟve immune response. ImmTACs are bispecific T cell engagers comprised of a monoclonal T cell receptor (mTCR) that binds anƟgen pepƟdes presented by major histocompaƟbility complex (pMHC) on transformed cells, and an anƟ-CD3 scFv that binds and acƟvates T-cells. The cancer testes anƟgen NY-ESO-1 is an ideal immunotherapy target due to restricted expression in healthy Ɵssue. However, ImmTACNYESO is currently restricted to HLA.A*02:01-posiƟve paƟents, thus >50% of the Caucasian populaƟon are refracƟve to this therapy. OncolyƟc viruses (OV) have potenƟal to induce cancer cell death, and this potenƟal can be enhanced when combined with radiotherapy, chemotherapy and immunotherapy. Adenoviruses (Ads) are aƩracƟve OVs due to their ease of manipulaƟon. Ad5NULL-A20 is a tumour-selecƟve, tropism-modified OV that exclusively infects tumour cells expressing αvβ6 integrin, a biomarker of aggressive HNC. Expression of Ad receptors and αvβ6 integrin in HNC is confirmed through flow cytometric and immunohistochemical analysis both in vitro and ex vivo. Exposure to IR did not reduce expression of these receptors and the radiosensiƟsing potenƟal of Ads was restricted to oncolyƟc variants. HNC paƟent derived organoids were established and explored as an ex vivo model for assessment of virus-directed enzyme prodrug therapy (VDEPT). In addiƟon, we demonstrated the selecƟvity of Ad5NULL-A20 to αvβ6 integrin, and confirmed successful engineering of HAdV-C5 and Ad5NULL-A20 to express ImmTAC-NYESO by western blot. Admediated expression of ImmTAC-NYESO did not result in T cell acƟvaƟon comparable to purified ImmTAC-NYESO. Through Ad-mediated expression of pHLA, we increase the number of cancer cells targeted by acƟvated T cells mediated by ImmTAC-NYESO. Overall, these studies demonstrate the potenƟal of OVs as a radiosensiƟser and the efficacy of Ad5NULL-A20 as a plaƞorm for VDEPT and in combinaƟon with immunotherapy. Further research is required to determine the efficacy and safety of these combinaƟons in vivo.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	17 January 2025
Last Modified:	17 Jan 2025 14:41
URI:	https://orca.cardiff.ac.uk/id/eprint/175332

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