Abstract LB380: A novel LNP-Encapsulated mRNA vaccine reshapes the immune microenvironment to overcome immunotherapy and chemotherapy resistance in esophageal squamous cell carcinoma with PIK3CA hotspot mutation

Abstract Chemotherapy plus PD-1 blockade as first line therapy significantly improves progression-free survival (PFS) and over all survival (OS) in patients with advanced esophageal squamous cell carcinoma (ESCC), yet part of patients fail to benefit from it continuously due to heterogeneous reasons. Based on our clinical trails JUPITER-06, PIK3CA was indentified as the negative effector for immunotherapy. Herein, this study reveals that a special subtype of myeloid cells characterized by poor potential of antigen presentation suppresses the infiltration of immune cells, primarily CD8+ T cells in PIK3CA-mutated tumors, and this process can be reversed by a novel LNP-Encapsulated mRNA vaccine with reshaping the tumor immune microenvironment and enhancing the therapeutic efficacy of immunotherapy. Our spatial transcriptomics analysis of single-cell resolution shows that an increased infiltration of neoantigen related antigen-presenting cells termed as “Neo-APCs” is significantly correlated with a spatial decrease in the infiltration of CD8+ T cells and tissue resident memory T cells (Trm) and predicts unfavorable clinical outcomes. Together with the analysis of Whole Exome Sequencing and RNA-seq performed on paired tumor tissues and blood samples, we successfully identified personalized neoantigens and the overlapping neoantigen peptides among cases with PIK3CA mutations under different HLA expression profiles. Correspondingly, in order to reverse the state of immune underactivation caused by insufficient antigen presentation in these cases, we developed an mRNA neoantigen vaccine for PIK3CA oncogenic related mutations targeting Neo-APCs. The vaccine is characterized by its stable expression from mRNA to neoantigen,its tremendous activation on immune system and its efficient delivery of mRNA, one made possible by a brand new formulation of lipid nanoparticles (LNPs). In the preclinical study with dual-humanized mouse models, the mRNA neoantigen vaccine shows efficacy and safety. After delivery, the mRNA modified in vitro to overcome inherent instability and immunogenicity, passes message of neoantigens from Neo-APCs to immune cells triggering anti-tumor responses. As the immunity cycle running, the immunosuppressive tumor microenvironment is reshaped with enhanced cytokine levels and increasing population of M1 macrophages, CD8+ T cells, Trm and so on. In addition, the vaccine synergizes with PD-1 blockade in ESCC. Similarly, in Patient-Derived Organoids (PDOs), this vaccine, in conjunction with Neo-APCs in a co-culture experiment, has also demonstrated promising therapeutic efficacy. In conclusion, this study introduced the pivotal role of Neo-APCs in esophageal cancer with PIK3CA mutations, leading to resistance to immunotherapy and an mRNA neoantigen vaccine was developed targeting Neo-APCs with successful immune response and anti-tumor effects, which potentiates a new therapy for patients suffered from drug-resistance to chemotherapy plus anti-PD-1 in ESCC. Citation Format: Feng Wang, Rui-Hua Xu, Yu Xu, Yue Huang, Yijun Gao. A novel LNP-Encapsulated mRNA vaccine reshapes the immune microenvironment to overcome immunotherapy and chemotherapy resistance in esophageal squamous cell carcinoma with PIK3CA hotspot mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB380.