Intratumoral administration of lipid nanoparticles carrying mRNA encoding for IL-21, IL-7 and 4-1BBL induces anti-tumor immunity in preclinical tumor models.

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)
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 a wide range of diseases including cancer. Local delivery of mRNA-based immunotherapy offers a promising avenue for personalized medicine as it enables the production of specific immunomodulatory proteins that can stimulate the immune system to recognize and eliminate cancer cells, showcasing encouraging results in preclinical tumor models while minimizing systemic side effects.
Efficient mRNA delivery is challenging due to its rapid degradation by ribonucleases and limited cellular uptake. Here, we developed and employed ionizable lipid nanoparticles (LNPs) to circumvent these issues. Intratumoral delivery of LNPs carrying Thy1.1-encoding mRNA showed higher Thy1.1 expression than naked Thy1.1 mRNA, indicating superior transfection efficiency in both immune and non-immune cells, with macrophages and cDC2s being the main cells taking up the LNPs.
We used the LNPs to deliver the cytokines interleukin (IL)-21 and IL-7 and the immunostimulatory molecule 4-1BB ligand (Triplet LNP) into subcutaneous MC38 tumors and employed CITE-Seq to decipher how the therapy alters the transcriptome of immune cells in the tumors. The Triplet LNP led to a profound increase in the frequency of tumor-infiltrating CD8⁺ T cells, their activation and cytotoxic capacity, leading to tumor eradication and the development of immunological memory against MC38 cancer cells. Mechanistically, we showed that the efficacy of the Triplet LNP was CD8⁺ T-cell dependent.
Ultimately, the Triplet LNP showed superior therapeutic efficacy to anti-PD1 against the orthotopic triple-negative breast carcinoma model E0771, highlighting the therapeutic potential of the Triplet LNP in multiple murine tumor models.

Period	16 Oct 2023
Event title	5th Research Day in Tumor Immunology and Immunotherapy
Event type	Conference
Location	Leuven, BelgiumShow on map
Degree of Recognition	International