Click chemistry-based tools to study therapeutic vaccines

Abstract

(Personalized) therapeutic vaccines hold great promise for the treatment of cancers by (re-)initiating an anti-tumor immune response. It is important that vaccine modalities used for personalized anti-cancer vaccination are relatively easy to prepare and highly modular, as each patient requires their own bespoke vaccine. Therefore, synthetic long peptides (SLPs) and mRNA-based vaccines have been established as the most promising modalities for these purposes. However, there are still several problems associated with both modalities that need to be overcome. Moreover, there is a disconnect between clinical observations and the underlying molecular mechanisms. Therefore, there is a need for novel methods to better understand SLPs and mRNA-based vaccines at the molecular level and correlate this to the subsequent immune responses. The research presented in this thesis focuses on developing several click chemistry-based methods and tools to study both SLPs and mRNA-lipid nanoparticles (LNPs). The methods were optimized and verified in multiple (primary) immunological models, and were shown to be compatible with commonly used antibody staining for immunophenotyping. The tools developed in this thesis hold great promise for the study of both MHC-I- and MHC-II-restricted epitopes within SLPs, and of multiple components of mRNA-LNPs, thereby providing the field with new chemical methods to study and understand the molecular mechanisms behind SLP- and mRNA-based therapeutic vaccines.