Development of a mRNA therapeutic vaccine for HPV-ve head and neck squamous cell carcinoma

This thesis aimed to develop a novel therapeutic cancer vaccine targeting HPV-ve HNSCC, with the goal of enhancing antitumour immunity.<br><br>Initial investigations focused on evaluating RALA peptide as a delivery system for various nucleic acids. Through physiochemical characterisation and functional assessments, RALA/mRNA nanoparticles (NPs) at an N:P ratio of 9 demonstrated optimal properties and superior protein expression compared to pDNA and saRNA.

Building on this, the project identified MAGEA4 as a promising tumour antigen for HPV-ve HNSCC via bioinformatics, and GM-CSF selected as an adjuvant. Both MAGEA4 and GM-CSF encoding mRNAs were synthesised and successfully encapsulated with RALA. The therapeutic efficacy of the RALA/mRNA-MAGEA4 vaccine was subsequently evaluated in a murine model of HPV-ve HNSCC.

The vaccine successfully elicited a robust T-cell-mediated immune response, characterised by increased IL-2 and IFN-γ production. This translated into significantly prolonged survival in vaccinated mice. While GM-CSF enhanced the immune response, the therapeutic efficacy remained inconclusive, highlighting its complex dual role in tumour immunity. <br><br>This research demonstrated the potential of RALA/mRNA-MAGEA4 NPs as a viable and effective therapeutic cancer vaccine platform for HPV-ve HNSCC.

The findings provided insights into non-viral mRNA delivery and antigen selection.<br><br><i>Thesis is embargoes until 31 December 2030.</i><br><br>