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Abstract mRNA immunotherapies have gained interest for the treatment of tumors from various origins, however, their ability to provide long -term durable tumor control has been underwhelming. Here we report that novel mRNA lipid nanoparticle (LNP) vaccinations induce robust expansion of antigen-specific T cells, although this does not always correlate with their ability to infiltrate and kill solid tumors. Using a portfolio of novel ionizable lipids and a robust in vivo model that reliably identifies LNPs with prominent anti-tissue T cell activity we have identified a putative LNP candidate that provides long term tumor control in a murine syngeneic tumor model. We utilized the model antigen glycoprotein (Gp), from the lymphocytic choriomeningitis virus (LCMV), and produced mRNA encoding the immunodominant epitopes gp3333-41, gp6161-80 and gp276276-286 (3GP-mRNA). This mRNA was encapsulated in various novel LNP formulations and administered i. m. into naïve C57Bl/6 mice to track the induction of a robust CD8+ T cell response identified using tetramers to gp33 and gp276. Successful candidate LNPs were then tested in the RIPgp model of autoimmune diabetes. RIPgp transgenic mice express LCMV-Gp in the pancreatic β cells and offer a robust assay for the ability to induce antigen-specific T cells capable of breaking self-tolerance and infiltrating and killing target tissue. Utilizing the RIPgp model to screen LNP candidates we identified a lead candidate, C2-5A, that both induced a robust expansion of antigen-specific T cells and tissue destruction. When utilized in a colon adenocarcinoma model expressing the LCMV-Gp antigen (MC38-Gp), therapeutic dosing of LNP C2-5A as a monotherapy lead to long term tumor clearance in 40% of the treated animals. We believe this screening platform allows the selection of LNP candidates capable of breaking self-tolerance, and one such candidate C2-5A provides a potent vehicle and adjuvant for mRNA based cancer vaccines. Citation Format: Douglas G. Millar, Matthew J. Gold, Kirsten Olsen, Yu Wu, Yury Karpov, Robert Nechanitzky, Haritha Menon, Rajesh Krishnan, Robert Georgantas, Pamela Ohashi, Natalia Martin-Orozco. Next-generation LNPs induce effective anti-tumor T cell responses abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6740.
Millar et al. (Fri,) studied this question.