mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells.

Autor:	Bevers S; eTheRNA Immunotherapies, 2845 Niel, Belgium; Laboratory for Molecular and Cellular Therapy (LMCT), Free University of Brussels, 1090 Jette, Belgium., Kooijmans SAA; CDL Research, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands., Van de Velde E; eTheRNA Immunotherapies, 2845 Niel, Belgium., Evers MJW; CDL Research, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands., Seghers S; eTheRNA Immunotherapies, 2845 Niel, Belgium., Gitz-Francois JJJM; CDL Research, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands., van Kronenburg NCH; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, the Netherlands., Fens MHAM; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, the Netherlands., Mastrobattista E; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, the Netherlands., Hassler L; CYBERnano, 54000 Nancy, France., Sork H; Institute of Technology, University of Tartu, 50411 Tartu, Estonia., Lehto T; Institute of Technology, University of Tartu, 50411 Tartu, Estonia; Department of Laboratory Medicine, Karolinksa Institutet, 141 52 Huddinge, Sweden., Ahmed KE; Department of Laboratory Medicine, Karolinksa Institutet, 141 52 Huddinge, Sweden., El Andaloussi S; Department of Laboratory Medicine, Karolinksa Institutet, 141 52 Huddinge, Sweden., Fiedler K; eTheRNA Immunotherapies, 2845 Niel, Belgium., Breckpot K; Laboratory for Molecular and Cellular Therapy (LMCT), Free University of Brussels, 1090 Jette, Belgium., Maes M; eTheRNA Immunotherapies, 2845 Niel, Belgium., Van Hoorick D; eTheRNA Immunotherapies, 2845 Niel, Belgium., Bastogne T; CYBERnano, 54000 Nancy, France; CRAN, Université de Lorraine, CNRS, INRIA BIGS, 54506 Vandœuvre-lès-Nancy, France., Schiffelers RM; CDL Research, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands., De Koker S; eTheRNA Immunotherapies, 2845 Niel, Belgium. Electronic address: stefaan.dekoker@etherna.be.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Sep 07; Vol. 30 (9), pp. 3078-3094. Date of Electronic Publication: 2022 Jul 12.
DOI:	10.1016/j.ymthe.2022.07.007
Abstrakt:	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. Competing Interests: Declaration of interests S.B., E.V.d.V., S.S., M.M., D.V.H., and S.D.K. are employees of eTheRNA Immunotherapies NV. S.B., S.A.A.K., R.M.S., and S.D.K. have applied for patents related to this study. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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