Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity.

Autor: Hamouda AEI; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Filtjens J; etherna, Ghent, Belgium., Brabants E; etherna, Ghent, Belgium., Kancheva D; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Debraekeleer A; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Brughmans J; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Jacobs L; etherna, Ghent, Belgium., Bardet PMR; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Knetemann E; Liver Cell Biology Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Lefesvre P; Department of Anatomo-Pathology, Universitair Ziekenhuis Brussel (UZB), Brussels, Belgium., Allonsius L; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Gontsarik M; Department of Pharmaceutics, University of Ghent, Ghent, Belgium., Varela I; etherna, Ghent, Belgium., Crabbé M; etherna, Ghent, Belgium., Clappaert EJ; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.; Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium., Cappellesso F; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Caro AA; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.; Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium., Gordún Peiró A; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.; Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium., Fredericq L; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.; Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium., Hadadi E; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.; Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium., Estapé Senti M; CDL Research, University Medical Center, Utrecht, The Netherlands., Schiffelers R; CDL Research, University Medical Center, Utrecht, The Netherlands., van Grunsven LA; Liver Cell Biology Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium., Aboubakar Nana F; Institut de Duve, Université Catholique de Louvain, Brussels, Belgium.; Service de Pneumologie, Cliniques Universitaires Saint-Luc, Brussels, Belgium., De Geest BG; Department of Pharmaceutics, University of Ghent, Ghent, Belgium., Deschoemaeker S; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium., De Koker S; etherna, Ghent, Belgium., Lambolez F; etherna, Ghent, Belgium. florence.lambolez@etherna.be., Laoui D; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium. dlaoui@vub.be.; Lab of Cellular and Molecular Immunology, Brussels Center for Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium. dlaoui@vub.be.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Dec 06; Vol. 15 (1), pp. 10635. Date of Electronic Publication: 2024 Dec 06.
DOI: 10.1038/s41467-024-54877-9
Abstrakt: Local delivery of mRNA-based immunotherapy offers a promising avenue as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells while limiting systemic exposure and toxicities. Here, we develop and employ lipid-based nanoparticles (LNPs) to intratumorally deliver an mRNA mixture encoding the cytokines interleukin (IL)-21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP). IL-21 synergy with IL-7 and 4-1BBL leads to a profound increase in the frequency of tumor-infiltrating CD8 + T cells and their capacity to produce granzyme B and IFN-γ, leading to tumor eradication and the development of long-term immunological memory. Mechanistically, the efficacy of the Triplet LNP depends on tumor-draining lymph nodes to tumor CD8 + T-cell trafficking. Moreover, we highlight the therapeutic potential of the Triplet LNP in multiple tumor models in female mice and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators is associated with better overall survival in patients with cancer.
Competing Interests: Competing interests: J.F., E.B., S.D.K., and F.L. are employees of etherna. J.F., E.B., S.D.K., and F.L. have applied for a patent related to the study (Compositions and methods for delivery of agents to immune cells; WO2023118411A1). S.D.K. and B.G.D.G. have applied for a patent related to the ionizable lipids used in this work (Ionizable lipids; WO2022136641A1). All other authors declare no potential conflicts of interest.
(© 2024. The Author(s).)
Databáze: MEDLINE
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