Therapeutic mRNAs offer great potential as a versatile and precise tool against cancer and other diseases. However, the therapeutic effectiveness is limited by the poor translation uptake of naked mRNA. To circumvent this challenge, researchers from VIB, VUB, Ghent University, and eTheRNA Immunotherapies developed an immunotherapeutic platform based on lipid-based nanoparticles (LNPs). In different cancer models, applying a novel mixture of immunotherapeutic mRNA encapsulated in LNPs led to a clearly improved therapeutic efficacy with limited side effects. This proves the added value of the platform to the development of effective mRNA immunotherapies.
The COVID-19 pandemic and recent Nobel Prize recognition have spotlighted mRNA therapies as a promising approach for diseases like cancer. With precision, scalability, and controlled immune activation, mRNA-based immunotherapy can encode proteins that stimulate the immune system to target and destroy cancer cells. Yet, naked mRNA is unstable, prone to degradation, and poorly absorbed by cells, limiting its effectiveness. This makes the development of reliable delivery methods essential for the future success of mRNA immunotherapies.
A trustworthy delivery tool
In the search for protecting therapeutic mRNA against degradation, the RNA technology company eTheRNA explored the possibility of encapsulating the mRNA in lipid-based nanoparticles (LNPs). To find the best formulation of LNP to bring mRNA into cells, the company teamed up with Dr. Bruno De Geest (Ghent University) because of his expertise in developing LNPs. The eTheRNA research team encapsulated a novel mixture of mRNA coding for three proteins (IL-21, IL-7, and 4-1BBL) in the selected LNPs.
Dr. Florence Lambolez, director Pharmacology at eTheRNA: "In our newly developed LNPs,the mRNAs encoding therapeutic proteins are protected against degradation during their intratumoral administration. This will improve the overall therapeutic efficacy."
Unraveling the mode of action
Dr. Damya Laoui and her team at VIB-VUB then tested the efficacy of the Triplet mRNA LNPs in various preclinical tumor models. The team found that the LNP was taken up by various cells within the tumor, including immune cells, such as dendritic cells. These cells could then produce high levels of the therapeutic proteins in the tumor, showing synergistic effects.
Ahmed Hamouda (VIB-VUB), first author of the study: "The dendritic cells that took up the LNPs, matured and moved to the lymph nodes where they activated T cells. In turn, the T-cells eliminated the cancer cells completely. We also showed that the Triplet mRNA LNP therapy didn't work in the absence of T cells."
Positive findings for future therapies
The results in mouse models are very promising. Next to an elimination - instead of an expected reduction - of the cancer cells, the Triplet LNP therapy showed reduced toxicity. The therapy was also effective in cancer models that show resistance to immune checkpoint blockade, the currently most used immunotherapy. As a first step from mice to men, the researchers proved in the lab that LNPs can also be taken up by human lung cancer cells.
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Dr. Damya Laoui (VIB-VUB): "It is great to see that our strategy to use LNPs to administer therapeutic mRNAs into the tumor, works. It stimulates the immune system to recognize and eliminate cancer cells, while limiting detrimental side effects. On top of that, it leads to immunological memory that protects against tumor rechallenge."
Dr. Stefaan De Koker, eTheRNA: "These results confirm the relevance of our immunotherapeutic platform to the development of future immunotherapies. Depending on the needs of different types of cancer, we can leverage our platform for various therapeutic mRNAs."
Funding
This research was supported by VLAIO, European Union's Horizon 2020 research and innovation program, FWO, FNRS, Kom op tegen Kanker, Stichting tegen Kanker, Vrije Universiteit Brussel, Ghent University, and VIB
Journal reference:
Hamouda, A. E. I., et al. (2024). Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity. Nature Communications. doi.org/10.1038/s41467-024-54877-9.