Immu-16. identification of tumor rejection antigens for precision adoptive cellular therapy for pediatric gliomas

Abstract BACKGROUND Identifying tumor rejection antigens remains a major barrier to developing effective antigen-directed immunotherapeutics and their application to pediatric brain tumors. Recent progress in the field of cancer immunogenomics has facilitated the search for tumor-specific antigens by applying comprehensive cancer genomics to tumor antigen discovery. Using a custom antigen prediction pipeline, we performed in silico antigen prediction across a broad array of antigen classes including neoantigens, tumor-associated antigens (TAAs), and fusion proteins for human and murine medulloblastoma tumors. We generated antigen-specific T-cells and validated the antigen-mediated immune responses for the development of precision adoptive cellular therapy. METHODS We evaluated WES and RNA-seq data from 170 medulloblastoma patients available through ICGC and performed a comprehensive immunogenomic analysis of subgroup-specific transcription profiles to identify candidate antigen targets. Antigen-specific T-cells were generated from healthy donor PBMCs stimulated against commonly recurring neoantigens and TAAs and immune response was evaluated using IFNγ secretion. Furthermore, we performed tumor antigen discovery for preclinical medulloblastoma models Ptch1 (sonic hedgehog driven) and NSC (Group 3 MYC-driven) and validated the antigen-mediated immune responses of ex vivo expanded antigen-specific T-cells. RESULTS Antigen prediction analysis revealed most tumors expressed a higher proportion of immunogenic TAAs than neoantigens and fusion proteins. The neoantigens and TAAs evaluated in this study showed significantly higher IFN-γ secretion in an antigen-dependent manner for both the human and murine platform validation. We thus confirmed the capability to produce functional tumor antigen-specific T-cells that can be leveraged into adoptive cellular therapy for the treatment of medulloblastoma. CONCLUSION Medulloblastomas are immunologically heterogeneous, and identifying potential tumor rejection antigens is desirable to develop personalized immunotherapies for the patients. Using a custom antigen prediction and ex vivo antigen-specific T-cell expansion pipeline, we identified potential tumor rejection antigens with important implications for the development of antigen-directed cellular therapies.