Abstract 866: Next-generation neoantigen vaccines powered by AI-assisted discovery and APC-targeted delivery platforms

Abstract Neoantigen-based cancer vaccines have shown promising efficacy in recent clinical trials for treating solid tumors. However, traditional neoantigen prediction methods, which largely rely on HLA-peptide binding databases, often yield false-positive predictions, highlighting the need for more accurate strategies to identify truly immunogenic neoantigens. To address this, we developed NEOVigator, an advanced neoantigen discovery platform that combines an AI-driven algorithm with functional validation using tumor-specific T cells derived from autologous tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs). The NEOVigator platform mimics the complete antigen presentation and T-cell response cascade by isolating and expanding autologous antigen-presenting cells (APCs) to evaluate neoantigen expression, processing, MHC binding, and presentation. Patient-derived TILs and PBMC T cells are then used to assess TCR recognition and T-cell responses to APC-presented antigens. Trained on experimentally validated immunogenic neoantigens, the AI algorithm achieves over 40% predictive accuracy across diverse solid tumor types. To enhance neoantigen delivery and maximize antitumor T-cell responses, we developed an APC-targeted lipid nanoparticle (LNP) system. This innovative mRNA delivery platform enables efficient, APC-specific targeting across multiple organs while minimizing off-target expression in non-immune cells, such as hepatocytes. Preclinical toxicology studies in multiple species have demonstrated favorable tolerability for both the ionizable lipid L52715 and the APC-targeted LNP formulation. Our lead neoantigen vaccine candidate, GT601, has successfully entered an investigator-initiated clinical trial in China, marking a major milestone in translating the NEOVigator platform into next-generation cancer immunotherapies. Citation Format: Jingwei Sun, Zhenjiang Liu, Ke Liu, Xi Zhu, Chenxi Hou, Hong Chen, Xu Wang, Jiahui Jin, Zhao Xu, Stephen Schoenberger, Pin Wang, Yarong Liu. Next-generation neoantigen vaccines powered by AI-assisted discovery and APC-targeted delivery platforms. [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 866.