Abstract 3532: Development of mouse models for preclinical evaluation of cancer mRNA vaccines

Abstract Since the successful development of vaccines against COVID, mRNA vaccine strategy showed superior efficacy and lower manufacturing costs compared to conventional vaccine approaches. The broad usage of mRNA vaccines was initially hampered by the early degradation before reaching to the target tissues. With the development of improved delivery systems to overcome the aforementioned problems in vivo, mRNA vaccine has become a promising strategy against various diseases including cancer. However, wild type mouse models are not suitable for the evaluation of cancer mRNA vaccines due to the fact that effective MHC-restricted antigen presentation is critical for mRNA vaccines to work in vivo in order to trigger a robust cellular and humoral immune response. GemPharmatech has developed a series of MHC-humanized mouse models to better evaluate the in vivo immunogenicity, efficacy and safety of mRNA vaccines, eliminating the inconsistencies in antigen peptide recognition and immune response due to the MHC structural discrepancies between humans and mice. Human immune cells can be reconstituted in immunodeficient mice (NCG) engrafted with human hematopoietic stem cells (HSC). However, since the species differences that murine cytokines provide limited support to human immune cells, HSC-NCG mice lack sufficient numbers of functional DC cells and the T cells are functionally defective because they are educated by murine MHC molecules. To address these two issues, we have introduced human HLA-A2 molecules into HSC-NCG-M mice, which is the ideal model for human myeloid cell reconstitution. HSC-NCG-M-hHLA-A2 mice have been developed to better reconstitute DCs and functional T cells educated by human MHC I molecules. An improved quantity of DC cells can be detected in HSC-NCG-M-hHLA-A2 mice. In addition, HLA-A2-restricted immune responses can be observed in HSC-NCG-M-hHLA-A2 mice. The HSC-NCG-M-hHLA-A2 mouse model is an ideal mouse model for the evaluation of in vivo immunogenicity and anti-tumor efficacy of mRNA cancer vaccines. In addition to the humanized models, the adoptive cell transfer mouse model, in which splenocytes from immunocompetent MHC-humanized mice are injected into tumor-bearing (HLA matched) immunodeficient mice, is also an excellent choice, utilizing the complete immune system of immunocompetent mice and the susceptibility of immunodeficient mice to human tumor cells. This is the ideal model for the evaluation of TAA targeting mRNA vaccines, which is time and cost efficient without the need for cell line modification. In conclusion, we have developed a series of MHC-humanized mouse models to provide more options for preclinical evaluation of tumor vaccines. Citation Format: Hongyan Sun, Jialu Fan, Yunlong Jiang, Jianming Xu, Xiang Gao, Jun Wang. Development of mouse models for preclinical evaluation of cancer 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 3532.