Abstract 78P
Background
Neoantigen-based mRNA vaccines, formulated as Chemically synthesized minimal mRNA (CmRNA) concatemers, offer potential in cancer immunotherapy by triggering specific T-cell responses. Leveraging lipid nanoparticle (LNP) technology can further augment personalized treatment strategies, particularly in combating colorectal cancer (CRC). Recent advancements in mRNA vaccine design and delivery, including the utilization of CmRNA, hold promise for enhancing the efficacy of immunotherapy against CRC.
Methods
Cutting-edge computational modeling tools, including Rosetta, PyMOL, and the Immune Epitope Database Analysis Resource (IEDB-AR), were utilized to optimize tumor-specific neoantigens into a single CmRNA) concatemer tailored for CRC. Detailed in silico analyses explored potential synergies by combining neoantigen-targeted mRNA vaccines with various natural Toll-like Receptor (TLR) Stimulating Adjuvants. Codon optimization algorithms and platforms such as CodonOptimizer and mRNA Architect were employed to refine vaccine constructs, enhancing translational efficiency and immunogenicity.
Results
Our study demonstrates that co-encapsulating CmRNA with natural polysaccharide-based adjuvants in LNP formulations triggers potent CD8+ T cell activation, suppresses CRC growth, and enhances the anti-tumor immune response. Computational analyses reveal the adjuvants' ability to activate macrophages via TLR4-mediated MAPK signaling, indicating their potential to modulate the tumor microenvironment. Additionally, the CmRNA-LNP complex exhibits robust stability and strong binding to MHC class I molecules, highlighting its therapeutic promise in CRC immunotherapy. Furthermore, in vivo studies demonstrate prolonged survival and reduced tumor burden in CRC mouse models treated with the CmRNA-LNP vaccine formulation.
Conclusions
Neoantigen-based CmRNA vaccines, combined with natural polysaccharide adjuvants in LNP formulations, show significant potential in enhancing T-cell responses against colorectal cancer. The robust stability and strong binding affinity of the CmRNA-LNP complex to MHC class I molecules further support its therapeutic potential in CRC immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This research was funded by the Talent Scientific Research Project of Zhejiang Shuren University for SABER IMANI, grant number KXJ1723104.
Disclosure
All authors have declared no conflicts of interest.