Abstract 3552: An mRNA-encoded adjuvant-enzyme activates STING to enhance the immunogenicity of vaccines targeting human papillomavirus positive cancers

Despite the clinical success of prophylactic vaccines against human papillomavirus (HPV), vaccines administered post-infection are unable to prevent HPV-associated cancers. Therapeutic HPV vaccines that can treat pre-malignant and established oropharyngeal and anogenital tumors therefore represent an unmet clinical need. Using a novel mRNA-encoded catalytic vaccine adjuvant, Corner Therapeutics is developing a therapeutic vaccine against HPV.The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway is a robust inducer of inflammation and protective immunity. No effective means to activate this pathway in the context of mRNA-based vaccines is known. Towards this end, we engineered an mRNA construct encoding a self-DNA reactive form of the enzyme cGAS (hereafter cGASΔN) to use as a catalytic vaccine adjuvant. Herein we show that cGASΔN mRNA was successfully formulated into lipid nanoparticles (LNPs) of a size and consistency matching LNPs used clinically, and that the cGASΔN mRNA is translated into a functional protein allowing for downstream STING signaling in primary human dendritic cells. When treated with cGASΔN mRNA-LNPs, human dendritic cells produced cytokines, chemokines and interferons, and expressed cell surface activation markers associated with T cell co-stimulation. The immunostimulatory activities of cGASΔN-LNPs resulted in robust ability of DCs to activate HPV-specific human T cells in in vitro cocultures. In contrast, DCs stimulated with LNPs encoding non-stimulatory proteins (akin to those used clinically), were ineffective inducers of T cell activation. In murine vaccination studies, intramuscular injection of LNPs encoding cGASΔN and HPV16 E6 and E7 antigens enhanced antigen-specific T cell responses to both viral proteins. These results establish cGASΔN mRNA-LNPs as a potent adjuvant to enhance the immunogenicity of mRNA-based HPV antigens, and that this promising approach could be utilized to develop therapeutic cancer vaccines. Citation Format: Jonathan Chow, Kelsey Finn, Anastasia Nikiforov, Dahlia Alkekhia, Stephan Matissek, Saisha Nalawade, Angela O'Neil, Carolyn MacFarlane, Philip Coblentz, Milap Chokshi, Colin Kelly, Brenna Sherbanee, Nicolina Lamberti, Evan Kennedy, Andrew Cornforth, Sivan Elloul, Jonathan C. Kagan. An mRNA-encoded adjuvant-enzyme activates STING to enhance the immunogenicity of vaccines targeting human papillomavirus positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3552.