Endogenous H3.3K27M derived peptide restricted to HLA-A∗02:01 is insufficient for immune-targeting in diffuse midline glioma
- Author(s)
- Wang, Stacie S; Pandey, Kirti; Watson, Katherine A; Abbott, Rebecca C; Mifsud, Nicole A; Gracey, Fiona M; Ramarathinam, Sri H; Cross, Ryan S; Purcell, Anthony W; Jenkins, Misty R;
- Journal Title
- Molecular Therapy Oncolytics
- Abstract
- Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape. We developed a second-generation CAR targeting an HLA-A?02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, binding to cells pulsed with the H3.3K27M peptide. However, we were unable to observe scFv binding, CAR T cell activation, or cytotoxic function against H3.3K27M+ patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3.3K27M26?35-HLA-A?02:01 peptide on these patient-derived models. Interestingly, other non-mutated peptides from DMG were detected bound to HLA-A?02:01 and other class I molecules, including a novel HLA-A3-restricted peptide encompassing the K27M mutation and overlapping with the H3 K27M26?35-HLA-A?02:01 peptide. These results suggest that targeting the H3 K27M26?35 mutation in context of HLA-A?02:01 may not be a feasible immunotherapy strategy because of its lack of presentation. These findings should inform future investigations and clinical trials in DMG.
- Publisher
- Elsevier
- Research Division(s)
- Immunology
- Publisher's Version
- https://doi.org/10.1016/j.omto.2023.08.005
- Open Access at Publisher's Site
https://doi.org/10.1016/j.omto.2023.08.005- Terms of Use/Rights Notice
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Creation Date: 2023-09-07 09:17:14
Last Modified: 2023-09-07 09:28:48