Abstract Glioblastoma is a highly aggressive brain tumor with limited therapeutic options. To enable precision cellular immunotherapy beyond classical surface antigens, we aimed to identify and validate glioblastoma-specific T-cell receptors (TCRs) targeting tumor-associated peptide - major histocompatibility complexes. We combined immunopeptidomics and single-cell TCR sequencing to identify tumor-specific antigens and corresponding reactive TCRs. Selected TCRs were cloned and introduced into primary human T cells. Engineered T cells were evaluated for antigen-specific activation and cytotoxicity in co-culture assays, glioma organoids, and orthotopic mouse models. Co-vaccination approaches with the cognate antigens were tested in vitro and in vivo. We isolated functional, antigen-specific glioblastoma-targeting TCRs. TCR-engineered T cells showed selective activation, cytokine production, and potent tumor cell killing in vitro. In organoid and in vivo models, engineered T cells infiltrated tumors, controlled tumor growth, and prolonged survival. Co-vaccination enhanced efficacy. These findings support further clinical development of strategies that target glioblastoma-associated peptide - major histocompatibility complexes. Citation Format: Lukas Bunse. Targeting tumor-associated peptide - major histocompatibility complexes in glioblastoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr IA006.
Lukas Bunse (Mon,) studied this question.