Abstract 2488: Employing RNA base editors to engineer personalized tumor-specific neoantigens

Abstract Enhancing the quantity and effectiveness of neoantigens in tumors is essential for advancing immunotherapy and developing targeted cancer vaccines. Crafting neoantigens presents a challenge due to the need to specifically modify peptide translation in tumor cells while avoiding effects on normal cells. To tackle this challenge, we introduce a novel method that enables the editing of selected nucleotides in the mRNA of cancer cells in order to produce potent neoantigens. The method is built on the use of Endogenous-ADAR base-editors, an established technology that allows for precise RNA-level edits, which is safer than DNA-level modifications and eliminates the need for external peptides by leveraging the native ADAR enzyme. The algorithm designs a guide RNA tailored to each tumor unique genetic profile and the patient’s HLA type, ensuring a precise and personalized approach to induce edits that are predicted to generate potent neoantigens in the cell. By targeting tumor-specific somatic mutations, our method ensures that edits are confined to tumor cells, sparing normal cells, thus offering a safer, more effective strategy for generating personalized neoantigens. We tested our computational algorithm on thousands of tumor samples available in The Cancer Genome Atlas (TCGA) database, demonstrating its capability to produce neoantigens across a broad spectrum of cases and cancer-types. As Endogenous-ADAR technology advances and delivery methods improve, the algorithm we present shows great promise as a valuable complement to immunotherapy and cancer vaccines. Citation Format: Rona Merdler-Rabinowicz, Netanel Landesman, Eytan Ruppin, Erez Levanon. Employing RNA base editors to engineer personalized tumor-specific neoantigens [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 2488.