Rapid-Turnaround Co-Administration of mRNA-Based MHC-I and MHC-II-Restricted Neoantigens Enhances Immune Responses of Antigen-Specific CD8 T Cells and Anti-Cancer Efficacy in Colorectal Cancer.

Personalized cancer vaccines (PCVs) represent a promising frontier in cancer immunotherapy; however, challenges in neoantigen prediction and treatment optimization persist. This study aims to introduce an innovative mRNA-based PCV platform that addresses these limitations. Co-administration of our major histocompatibility complex (MHC)-I and MHC-II-restricted neoantigens increases antigen-specific T cell responses and exhibits strong anti-cancer efficacy, significantly inducing antigen-specific CD8 T cell-immune responses. The mRNA-based vaccine targeting the novel antigens demonstrates anti-tumor efficacy in a murine model of colorectal cancer and reduces post-surgery recurrence in mRNA-vaccinated mice. Notably, early-stage vaccination induces a striking anti-cancer effect, underscoring the critical role of MHC-II neoantigens alongside MHC-I antigen prediction in shaping effective anti-tumor immunity, in the activation of antigen-specific CD8 T cells. In addition, the combination of immune checkpoint inhibitors and the vaccine synergistically inhibits tumor growth by inducing robust T cell responses and promoting favorable alterations in the tumor microenvironment. Taken together, the results provide a strong rationale for the clinical investigation of rapid-turnaround co-administration of MHC-I/II-restricted neoantigens-based mRNA vaccines in colorectal cancer, as supported by the anti-tumor efficacy of early-stage application and combination immunotherapy approaches.