Fiche publication
Date publication
juillet 2022
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BASTOGNE Thierry
Tous les auteurs :
Bevers S, Kooijmans SAA, Van de Velde E, Evers MJW, Seghers S, Gitz-Francois JJJM, van Kronenburg NCH, Fens MHAM, Mastrobattista E, Hassler L, Sork H, Lehto T, Ahmed KE, El Andaloussi S, Fiedler K, Breckpot K, Maes M, Van Hoorick D, Bastogne T, Schiffelers RM, De Koker S
Lien Pubmed
Résumé
mRNA vaccines have recently proven to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP based antitumor immunotherapy.
Référence
Mol Ther. 2022 07 11;:
