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Tonic Signaling Shaped by Epitope Targeting Governs CAR-T Cell Fitness and Antitumor Activity in Diffuse Midline Glioma [CUT&Tag]

GSE302513 Homo sapiens Genome binding/occupancy profiling by high throughput sequencing 4 samples Submitted 2025/12/04 Platform GPL24676
Summary
We systematically evaluated B7-H3–targeting CAR-T cells derived from three monoclonal antibodies (376.96, MGA271, and Hu8H9) in diffuse midline glioma (DMG or DIPG), a fatal pediatric brain tumor. Among these, 376.96 CAR-T cells had markedly lower tonic signaling, diminished expression of exhaustion markers, and enhanced tumor killing, cytokine production, and persistence. Transcriptomic and epigenomic profiling revealed a restrained activation state with reduced tonic signaling pathways and elevated stemness properties, oxidative metabolism, and innate immune sensing in these cells. In patient-derived spheroids and orthotopic DIPG xenografts, mRNA-based 376.96 CAR-T cells achieved robust tumor control and extended survival. By leveraging epitope selection, we reveal a mechanistic link between tonic signaling and CAR-T cell exhaustion, and provide a rational framework for optimizing CAR-T cell design to achieve improved efficacy and durability in pediatric brain tumor therapy.
Published in
A Tonic Signaling Code Predicts CAR-T Cell Efficacy in Diffuse Midline Glioma
Deng EB, Zhong X, Xin D et al. · bioRxiv : the preprint server for biology 2025 · PMID 41256549 · doi:10.1101/2025.09.29.679095
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Also filed as BioProject PRJNA1291105 and SRA study SRP600762. Searching any of these in the dataset finder brings you back here.

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