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

Hamouda, A. E. I. (Speaker)
Jessica Filtjens (Contributor)
Elisabeth Brabants (Contributor)
Kancheva, D. (Contributor)
Debraekeleer, A. (Contributor)
Brughmans, J. (Contributor)
Lotte Jacobs (Contributor)
Bardet, P. (Contributor)
Ismael Varela (Contributor)
Marian Crabbé (Contributor)
Emile Clappaert (Contributor)
Allonsius, L. (Contributor)
Hadadi, E. (Contributor)
Mariona Estapé Senti (Contributor)
Raymond Schiffelers (Contributor)
Stefaan De Koker (Contributor)
Bruno De Geest (Contributor)
Deschoemaeker, S. (Contributor)
Florence Lambolez (Contributor)
Laoui, D. (Contributor)

Activity: Talk or presentation › Talk or presentation at a conference

Description

Therapeutic mRNA demonstrated remarkable potential in tackling various diseases including cancer. 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 developed and employed 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 led 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, we found that within the immune cells, the mRNA transfection efficiency of intratumorally-delivered LNPs was highest in macrophages, monocytes and cDC2s, inducing the activation and migration of the latter to the tumor-draining lymph nodes (tdLNs). Differential Nichenet analysis on the scRNA-seq datasets of Triplet LNP-treated and control tumors predicted that upon therapy, mainly cDC2s and migDCs induced cytotoxic CD8⁺ T cells in the tdLNs. Moreover, we showed that the efficacy of the Triplet LNP was dependent on tdLN-tumor CD8⁺ T-cell trafficking and that the presence of CD39⁺ CX3CR1⁺ tumor-specific CD8⁺ T cells in the blood could be used as a prognostic factor for the response to Triplet LNP therapy. Finally, we highlight the therapeutic potential of the Triplet LNP in multiple murine tumor models and its superior therapeutic efficacy to immune checkpoint blockade. Ultimately, the expression of these immunomodulators was associated with better overall survival in cancer patients.

Period	20 Oct 2024 → 23 Oct 2024
Event title	17th International Symposium on Dendritic Cells
Event type	Conference
Location	Sitges, Spain
Degree of Recognition	International