Endogenous Retrovirus Neoantigen Enables Personalized Cancer Vaccine in glioblastoma, IDH-wildtype 2259068

Abstract Introduction Glioblastoma (GBM) remains refractory to immunotherapy due to low mutational burden and limited neoantigens. Aberrant expression of endogenous retroviral elements (ERVs), reactivated insertions of ancient viruses within the genome, may provide a source of tumor-specific antigens for personalized vaccines targeting traditional and ERV-derived neoantigens. Methods Tumor and matched normal tissues from 25 GBM patients, including 18 long-term survivors (LTS; >5 years) and 7 short-term survivors (STS; 12—18 months), underwent whole-genome and RNA sequencing. Candidate antigens were predicted using two AI-based pipelines: one for mutation-derived neoantigens and one for ERV-derived antigens. Predicted epitopes were ranked by expression, MHC class I and II binding affinity, clonality, and immunogenicity. Top candidates informed the design of a personalized DNA vaccine encoding 10 patient-specific neoantigen sequences with a CCL19 adjuvant to enhance dendritic cell recruitment. Results High-quality canonical neoantigens were rare (median 3/ patient), consistent with prior reports. Yet, all tumors expressed abundant, patient-specific ERV transcripts independent of mutation load. ERV-derived epitopes exhibited strong predicted MHC class I and II binding, comparable to viral antigens, with 22 of 25 tumors containing ERV peptides suitable for vaccine inclusion. These mapped primarily to HERV-K and HERV-W families and frequently overlapped interferon-stimulated loci. Comparison of LTS and STS cohorts is ongoing to define ERV expression patterns associated with durable immune control. Conclusion ERVs are consistently expressed and immunogenic in GBM, representing a scalable, tumor-specific antigen source that may overcome limitations of low mutational burden. These data provide a proof-of-concept for personalized vaccines targeting ERV-derived neoantigens. Funding Source Duke Brain Tumor Omics Program Fellow Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)