Recent advances in ribonucleic acid (mRNA) vaccine development, including the success of COVID-19 mRNA vaccines, have been recognised by the Nobel Prize in Physiology and Medicine 2023. Currently, there are 17 clinical trials for anticancer mRNA vaccine; however, none of them is specifically for GPC2-positive tumours, including neuroblastoma (paediatric cancer) and lung cancer, demonstrating the gap in the anti-cancer vaccine development pipeline for adults and children.
This project aims to develop the first mRNA vaccine against these cancers. We will build upon our recent data demonstrating the high immunogenicity of the selected full-length antigen delivered using RALA peptide. Specifically, we will focus on the selected antigen parts called exons to be individually targeted in a mRNA vaccine. We will perform an exon screening to verify their cancer-specific expression and to provide a rationale for their targeting. The RALA/mRNA nanoparticles will be characterized for shape, surface charge, stability and immunogenicity. The transfection efficiency of the vaccine will be determined in vitro using DC 2.4 cells (murine dendritic cells) and THP-1 cells (human monocytes). C57 BL/6 mice will receive the vaccine for the immunogenicity studies, and blood samples will be collected to analyse specific antibodies and cytokine secretion. The therapeutic potential of the RALA/mRNA vaccine will be analysed using a metastatic cancer mouse model. Finally, we will evaluate a rationale for combination therapy targeting key pathways in a characteristically synergistic or additive manner using Vorinostat, an FDA-approved member of histone deacetylase inhibitors (HDACi) with a broad spectrum of epigenetic activities. Finally, we will evaluate the regulatory options to ensure an efficient therapy translation to the clinical setting. This will include market analysis, intellectual property, and orphan drug designation applications.