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

Ahmed E. I. Hamouda, Jessica Filtjens, Elisabeth Brabants, Daliya Kancheva, Ayla Debraekeleer, Jan Brughmans, Lotte Jacobs, Pauline M. R. Bardet, Elisabeth Knetemann, Pierre Lefesvre, Lize Allonsius, Mark Gontsarik, Ismael Varela, Marian Crabbé, Emile J. Clappaert, Federica Cappellesso, Aarushi A. Caro, Alícia Gordún Peiró, Luna Fredericq, Eva Hadadi, Mariona Estapé Senti, Raymond Schiffelers, Leo A. Grunsven, Frank Aboubakar Nana, Bruno G. Geest, Sofie Deschoemaeker, Stefaan Koker, Florence Lambolez () and Damya Laoui ()
Additional contact information
Ahmed E. I. Hamouda: VIB Center for Inflammation Research
Jessica Filtjens: etherna
Elisabeth Brabants: etherna
Daliya Kancheva: VIB Center for Inflammation Research
Ayla Debraekeleer: VIB Center for Inflammation Research
Jan Brughmans: VIB Center for Inflammation Research
Lotte Jacobs: etherna
Pauline M. R. Bardet: VIB Center for Inflammation Research
Elisabeth Knetemann: Vrije Universiteit Brussel (VUB)
Pierre Lefesvre: Universitair Ziekenhuis Brussel (UZB)
Lize Allonsius: VIB Center for Inflammation Research
Mark Gontsarik: University of Ghent
Ismael Varela: etherna
Marian Crabbé: etherna
Emile J. Clappaert: VIB Center for Inflammation Research
Federica Cappellesso: VIB Center for Inflammation Research
Aarushi A. Caro: VIB Center for Inflammation Research
Alícia Gordún Peiró: VIB Center for Inflammation Research
Luna Fredericq: VIB Center for Inflammation Research
Eva Hadadi: VIB Center for Inflammation Research
Mariona Estapé Senti: University Medical Center
Raymond Schiffelers: University Medical Center
Leo A. Grunsven: Vrije Universiteit Brussel (VUB)
Frank Aboubakar Nana: Université Catholique de Louvain
Bruno G. Geest: University of Ghent
Sofie Deschoemaeker: VIB Center for Inflammation Research
Stefaan Koker: etherna
Florence Lambolez: etherna
Damya Laoui: VIB Center for Inflammation Research

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54877-9

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