EWSR1 fusion neoantigen vaccine for the treatment of recurrent Ewing sarcoma 9402

Abstract Description Ewing sarcoma (ES) is a highly aggressive childhood cancer with poor survival rates, particularly when metastasized. The key genetic event that drives ES tumorigenesis is a highly conserved gene fusion, EWSR1-FLI1, present in 90% of ES patients. We hypothesize that by utilizing EWSR1 fusion-derived neoantigens, a vaccine can be tailored to trigger an immune response against these neoantigens expressed by ES cells. Our objective is to develop an optimal vaccine and elucidate the immunological activity of this vaccine in ES patients in our trial. Using an HLA binding assay and mass spectrometry, we identified fusion-derived 204 peptides with HLA binding assay and 44 peptides with mass spectrometry presented in the context of various most common HLA alleles. Using IFNg ELISPOT, we confirmed T cell activation and immunogenicity in 44 HLA-peptide combinations. We also validated peptide immunogenicity by in vivo vaccination of long peptides in HLA transgenic mice. With our extensive findings, we designed an mRNA vaccine, and we’ll test it in a phase I clinical trial for the treatment of ES patients who currently have no effective treatment options. Our vaccine strategy holds the potential to not only amplify existing neoantigen-specific T cell populations but also to instigate a broader array of new T cell specificities, thereby shifting the balance within the tumor microenvironment toward enhanced tumor control and giving hope in the challenging landscape of pediatric oncology. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)