Abstract 3530: Utilizing a humanized HLA-A2.1 mouse model for non-clinical studies of mRNA vaccines

Abstract Substantial genetic discrepancies exist between the major histocompatibility complex (MHC) systems of animals and the human leukocyte antigen (HLA) system. The utilization of HLA humanized mouse model systems constitutes a superior methodology for examining fundamental mechanisms associated with HLA-A-related vaccine development and HLA-A-restricted immune responses against diseases such as infections and cancers in humans. To study both in vitro and in vivo the requirements for shaping an effective T cell response against clinically relevant cancer targets such as NY-ESO-1, WT1 and other newly discovered targets, Biocytogen generated a C57BL/6 background HLA-A2.1 humanized mouse model that is restricted to the human HLA-A2. This humanized mouse model was utilized to evaluate immune responses to a variety of cancer peptide and mRNA vaccines, including analyses of immune cell populations, cytokine production, and in vivo anti-tumor efficacy. Immunoprofiling analysis of this novel humanized HLA-A2.1 mouse strain revealed that the introduction of the HLA-A2.1 gene significantly influences the immune cell composition in these humanized mice. Following vaccination with various cancer-specific epitopes, HLA-A2.1-restricted, epitope-specific cytotoxic T lymphocytes (CTLs) were induced in the B-HLA-A2.1 mouse model. Furthermore, we established an mRNA vaccination treatment model in B-HLA-A2.1 mice, demonstrating a synergistic antitumor effect when combined with the mRNA vaccine. These findings indicate that the B-HLA-A2.1 mouse model serves as a powerful research tool, not only for investigating HLA-A2.1-restricted CTL responses but also for the preclinical evaluation of vaccines. We have established a promising preclinical research model using HLA-A2.1 humanized mice. This model could accelerate the identification of novel HLA-A2.1-restricted epitopes and facilitate vaccine development, while also supporting the study of HLA-A2.1-restricted responses against cancers in humans. Citation Format: Leila Kokabee, Zhenlan Niu, Jing Guo, Shuaiqiang Zhang, Zhiyuan Shen, Hui Xu. Utilizing a humanized HLA-A2.1 mouse model for non-clinical studies of mRNA vaccines [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 3530.