Novel dendritic cells-targeting mRNA-LNP vaccine with potent anti-tumor activity in vivo.

e21514 Background: Cancer vaccines have demonstrated limited efficacy in solid tumors with low immunogenicity. As the main antigen presenting cells, Dendric Cells (DCs) are crucial for initiating anti-tumor immune responses, both CD8+ cytotoxic T cells and CD4+ helper T cells. While ex vivo DC-based vaccines offer high specificity and efficiency, their clinical translation is hindered by the complexity of patient sample handling and high costs. Methods: We developed DKure, a novel platform to deliver tumor antigens to DCs in vivo using antibody-conjugated mRNA-LNPs. DKure is designed to have an antibody conjugated on the surface of LNP to target CLEC9A, a group V C-type lectin-like receptor (CTLR) that functions as an activation receptor and is expressed on DCs. Results: Using DKure, we demonstrate that CLEC9A-LNP encapsulated with TRP-2 mRNA significantly suppressed tumor growth in a B16 melanoma mouse model. The tumor inhibition of CLEC9A-LNP/TRP2 is 50% higher than that of unconjugated TRP2 LNP at day 16 post tumor inoculation. CLEC9A-LNP/TRP2 treated mice have 100% survival rate compared to 50% survival rate of unconjugated TRP2 LNP at day 18 post tumor inoculation. Tumor suppressive effects of CLEC9A-LNP/TRP2 are found to be highly correlated with TRP2 specific CD4 and CD8 T-cell activation and DC cell maturation in lymph nodes. Biodistribution studies demonstrated CLEC9A-LNP/TRP2 achieved extrahepatic uptake with enhanced delivery to the spleen and lymph nodes. Conclusions: Thus, DC-specific vaccines delivered with mRNA-LNP stimulates therapeutically effective tumor-specific immunity, offering a novel, efficient and cost-effective cancer vaccine strategy. DKure could serve as a potent platform for personalized cancer vaccine when incorporating neoantigen mRNAs from cancer patients.