| Summary: | Melanoma is the least common type of skin-cancer but the deadliest one. Cancer immunotherapy is considered a powerful tool in cancer treatment. Nevertheless, therapeutic cancer vaccines have led so far to modest immune responses with little clinical impact. The first part of this work is focused on developing a personalized melanoma vaccine platform based on VLPs and copper-free click chemistry, enabling bedside production of personalized cancer vaccines. There is currently a debate in the field whether cancer-specific, non-mutated germ-line epitopes or mutated neo-epitopes are more powerful antigens for vaccination. To address this issue, we identified melanoma-specific germ-line T-cell epitopes by immunopeptidomic and neoantigens using exome sequencing. Different VLP-based vaccine cocktails were generated, and their immunogenecity was compared in melanoma murine models. We demonstrate that both neoantigens and germ-line epitopes can induce partial protection, but the best therapeutic effect is achieved when combining both. The second part of the thesis tested a new adjuvant microcrystalline tyrosine (MCT) in combination with VLP-based vaccine (CuMV<sub>TT</sub>). MCT, is an adjuvant that has been used in licensed allergen-immunotherapy products for decades. The adjuvant potential of MCT was also compared to Alum and B-type CpGs. MCT was similarly potent as CpGs and clearly superior to Alum when CD8<sup>+</sup> T-cell responses and tumour protection were assessed. Combining a micron-sized adjuvant (MC) with nanoparticles (CuMVTT) appears a particularly attractive strategy as it optimally harnesses the drainage properties of the immune system. Thus, MCT may not only be used in marketed allergy products but may also be promising for induction of protective CTL response. Finally, we focused on delivering antigens and adjuvants in separate virus-like particles. This new technique would be beneficial when designing a personalized VLP-based vaccine as it would be handy to have a ready adjuvanted VLP which can be formulated with the patient vaccine at bed-side.
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