mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells
| Autor: | Bevers, Sanne, Kooijmans, Sander A.A., Van de Velde, Elien, Evers, Martijn J.W., Seghers, Sofie, Gitz-Francois, Jerney J.J.M., van Kronenburg, Nicky C.H., Fens, Marcel H.A.M., Mastrobattista, Enrico, Hassler, Lucie, Sork, Helena, Lehto, Taavi, Ahmed, Kariem E., El Andaloussi, Samir, Fiedler, Katja, Breckpot, Karine, Maes, Michael, Van Hoorick, Diane, Bastogne, Thierry, Schiffelers, Raymond M., De Koker, Stefaan, Afd Pharmaceutics, Pharmaceutics |
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| Přispěvatelé: | Laboratory of Molecullar and Cellular Therapy, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, Afd Pharmaceutics, Pharmaceutics |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
LNP
mRNA mRNA-LNP vaccines design-of-experiments methodology infectious diseases Cancer Vaccines Drug Discovery Genetics Animals cancer Tissue Distribution RNA Messenger Molecular Biology antitumor Pharmacology extrahepatic delivery SARS-CoV-2 Vaccination COVID-19 vaccination lipid-based nanoparticlelipid-based nanoparticle immunity oncology Nanoparticles Molecular Medicine Immunization immunotherapy Vaccine Spleen |
| Zdroj: | Molecular Therapy, 30(9), 3078. Cell Press |
| ISSN: | 1525-0016 |
| Popis: | mRNA vaccines have recently proved 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 to be 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. |
| Databáze: | OpenAIRE |
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