{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE337nnn/GSE337350/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE337350"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Brain-sensing synNotch-CAR T-cells enable precise targeting and clearance of diffuse midline glioma in multiple preclinical models","description":"Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with limited therapeutic options and a poor prognosis. The ultimate success of chimeric antigen receptor (CAR) T-cell therapy requires improving T-cell tumor infiltration, and persistence, and reducing the risk of on-target/off-tumor toxicity. Here, we adapt and advance a brain-restricted CAR T-cell platform, previously validated in glioblastoma, to address the distinct anatomical and biological challenges of DMG. We engineer we test whether a strategy developed for glioblastoma can also be effective against DMG. We evaluated a T- cell circuit in which a brain-specific sensor -- the synthetic Notch (synNotch) receptor recognizingagainst Brevican (BCAN) -- induces CAR the expression against of a CAR targeting either EphA2 or IL-13Rα2 (“B-SYNC”), enabling multi-antigen tumor recognition tumor recognition through multiple antigens while restricting CAR expression to the CNS. In immunodeficient DMG models, a single infusion of B-SYNC T- cells, either by intravenousintravenously (IV) or intracerebroventricularly (ICV) infusion, led to tumor infiltration, sustained persistence, robust anti-tumor activity, and significantly extended survival. An alternative BCAN-primed circuit CAR inducing a CAR targeting eithertargeting B7-H3 or IL-13Rα2 (“B-SYNC-B/I”) similarly improved therapeutic efficacy when delivered IV. However, ICV administration triggered fatal neurotoxicity due to low-level B7-H3 expression in non-tumor CNS regions, indicating that rapid CNS exposure via ICV delivery can amplify off-tumor toxicity. In contrast, in an immunocompetent syngeneic DMG model, both IV and ICV delivery of a murinized BCAN-gated B7-H3 CAR (mB-SYNC-B7-H3) achieved durable tumor clearance and resistance to rechallenge, without any detectable neurotoxicity. Mechanistically, synNotch-primed CAR T--cells exhibited reduced exhaustion, enhanced activation, and enrichment of naïve and stem- cell memory-like subsets. , supporting superior functional durability in the DMG microenvironment. These findings demonstrate that brain-sensing synNotch CAR T circuits represent a generalizable and translatable strategy for targeting multiple CNS malignancies, including DMG.","dates":{"publication":"2026/07/09"},"accession":"GSE337350","cross_references":{"GSM":["GSM9853639","GSM9853628","GSM9853617","GSM9853629","GSM9853618","GSM9853637","GSM9853626","GSM9853638","GSM9853627","GSM9853635","GSM9853624","GSM9853625","GSM9853636","GSM9853622","GSM9853633","GSM9853634","GSM9853623","GSM9853620","GSM9853631","GSM9853632","GSM9853621","GSM9853640","GSM9853630","GSM9853619"],"GPL":["34284"],"GSE":["337350"],"taxon":["Homo sapiens"]}}