bims-malgli 2026-08-02 papers

Neuro Oncol. 2026 Jul 25. pii: noag171. [Epub ahead of print]

Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.

BACKGROUND: High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy.
METHODS: BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival.
RESULTS: Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response.
CONCLUSIONS: Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.

Keywords: B7-H3; B7-H3 CAR T cells; CD276; H3 K27-altered (DMG); atypical teratoid rhabdoid tumor (ATRT); chimeric antigen receptor (CAR) T cells; diffuse midline glioma; ependymoma; high grade glioma (HGG); medulloblastoma

DOI: https://doi.org/10.1093/neuonc/noag171

medRxiv. 2026 Jul 22. pii: 2026.07.20.26358470. [Epub ahead of print]

Germline Variants in Centromere Binding Protein 126 Predispose to Glioblastoma.

Paul Renauer, Bianca-Maria Marin, Adrian Melo-Carrillo, Mindy Carpenter, Linbin Zhang, MacLean Nasrallah, Jennifer Morrissette, Steven Brem, Yuan Rong, Alex M Miller, Daniel A Orringer, Matthew Bainbridge, Melissa Bondy, Sidi Chen, Roel G W Verhaak.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. While only 5% of GBM cases arise in a familial context, the genetic basis of familial GBM remains unresolved in most affected clusters, suggesting that important susceptibility variants may reside outside recognized cancer-predisposition genes. Proband-based genomic studies of such families provide a rational path to discover rare inherited variants with large biological effects, prioritize candidate genes for functional validation, and define early mechanisms of gliomagenesis that may not be apparent from studies of sporadic tumors alone.
Methods: In this study, we investigated a family with GBM clustering spanning two generations. To investigate the possibility of shared germline susceptibility, we enrolled the proband and their two confirmed affected relatives in our study and performed whole-genome sequencing on available whole blood and tumor samples. Rare coding variants shared among the three study participants were identified and the genes harboring these variants were functionally interrogated with pooled loss-of-function CRISPR screens in human neural progenitor cells (NPCs) in vitro and in heterotopic xenograft models.
Results: Rare coding variants were identified in 139 candidate genes, and functional genetic screens of human NPCs in heterotopic xenograft models revealed Centrosomal Protein of 126 kDa (CEP126), as the top hit. Genetic disruption of CEP126 conferred a survival and tumorigenic advantage in neural progenitor cells.
Conclusion: Together, our results establish a functional framework for interrogating rare cancer germline variants and highlights CEP126 as a biologically tractable GBM predisposition gene for future mechanistic and genetic validation.

DOI: https://doi.org/10.64898/2026.07.20.26358470

Sci Transl Med. 2026 Jul 29. 18(860): eaeg8772

Glioblastoma: Overcoming fundamental biological and delivery barriers to therapy.

Genaro R Villa, Ashish D Patel, David A Reardon, E Antonio Chiocca.

Glioblastoma remains the most aggressive primary malignant brain tumor in adults, with survival largely unchanged despite advances in molecular diagnostics and supportive care. Therapeutic failure reflects fundamental biological and anatomical barriers, including intratumoral heterogeneity, an immunosuppressive tumor microenvironment, and restricted drug delivery across the blood-brain barrier. In this Review, we summarize the current standard of care and critically examine emerging strategies aimed at overcoming these constraints, including locoregional delivery technologies, immunotherapy, biomarker-defined precision approaches, and adaptive clinical trial designs. We highlight key translational and clinical studies shaping the field and discuss principles for developing more effective, integrated therapeutic paradigms.

DOI: https://doi.org/10.1126/scitranslmed.aeg8772

Nat Protoc. 2026 Jul 28.

Core2Edge: a human glioblastoma organoid-brain slice model capturing infiltration and transcriptional heterogeneity from core to single-cell dispersion.

Glioblastomas function as intricate cellular networks that extend into the surrounding brain tissue, facilitating long-distance communication. This malignant connectivity spans from the tumor core to remote infiltration zones, in support of the concept of glioblastoma as a whole-brain disease. With growing ethical concerns in biomedical research and the inherent limitations of animal models in recapitulating human glioblastoma biology, there is an increasing demand for human ex vivo platforms capable of capturing the full infiltration spectrum from the tumor core to single-cell dispersion. Here we present a 3D, fully human ex vivo glioblastoma model (Core2Edge) that replicates this extensive infiltration range while preserving the intratumoral heterogeneity of the original tumor. This model involves implanting fluorescently labeled human glioblastoma organoids (GBOs) into organotypic human brain slices, maintaining the genetic integrity and cytoarchitecture of both brain and tumor. By combining tissue expansion with light-sheet fluorescence microscopy, we achieve high-resolution, 3D imaging of the entire GBO-brain slice model. This approach allows the study of initial infiltration steps, in-depth analysis of the invasive front, and exploration of cell-cell interactions between tumor cells and the tumor microenvironment, and offers a platform for drug screening and testing, reducing the need for animal models. Once GBOs are prepared, the protocol takes ~7-12 d. Key steps include brain slice preparation (~4-6 h, depending on quantity), 1 d for initial culture before GBO staining and transplantation, a variable culture period (≤10 d), and fixation (~8 h). The protocol requires experience with human brain slice and organoid culture.

DOI: https://doi.org/10.1038/s41596-026-01412-3

Sci Transl Med. 2026 Jul 29. 18(860): eaeg9138

The neuroscience of childhood brain cancers.

Michelle Monje.

Nervous system activity drives both normal neurodevelopment and childhood brain cancers through paracrine and synaptic signaling. In childhood gliomas, cancer cells integrate structurally and electrically into neural networks, and neuron-cancer interactions are strongly growth-promoting. Understanding the neuroscience mechanisms regulating childhood brain cancers opens a previously unexplored avenue for much-needed therapeutic interventions.

DOI: https://doi.org/10.1126/scitranslmed.aeg9138