Year: 2019
Type: dissertation
Abstract: In the last three decades, an improved understanding of the mRNA pharmacology, together with novel insights in immunology have positioned mRNA-based technologies as next-generation vaccines. In this thesis, the specific aim was to design an mRNA vaccine for cancer immunotherapy with potential to evoke cytotoxic T cell responses against established tumors. In general, the success of an mRNA vaccine formulation will be determined on its capacity to deliver mRNA into antigen presenting cells, enabling transient production and presentation of mRNA-encoded antigens for T cell priming. In addition, the mRNA vaccines that are currently being evaluated in first-in-human trials depend on a self-adjuvant effect, associated with a type I interferon (IFN) response. However, this type I IFN immune cascade has the downside of inducing anti-mRNA (anti-viral) reactions, which makes it challenging to strike a balance between evoking a robust immune activation and obtaining adequate levels of mRNA expression. The first part of this research focused on the development of a lipid nanoparticle for the systemic delivery of mRNA to antigen presenting cells. Next, we hypothesized that it could be of benefit to uncouple the translation and type I IFN activities of mRNA vaccines, and to replace the type I IFN response by another, but “smarter” adjuvant. As such, we proposed a novel nanovaccine for the co-delivery of “immunosilent” mRNA and the natural killer T cell activator α-GalCer. We were able to demonstrate that this GALSOME approach holds advantages over state-of-the-art mRNA vaccines, by providing a controllable, multifaceted, and effective antitumor immunity, especially when combined with checkpoint therapy.
Author: R Verbeke
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2968025533