bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–08–16
eight papers selected by
Oltea Sampetrean, Keio University
  1. Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma.
  2. Histone H3K27M variants determine myeloid subset dependencies and immune reprogramming in diffuse midline glioma.
  3. Shifting AAV9 tropism by binding moiety insertion enhances transduction of tumor cell lines and human glioblastoma explants.
  4. Siglec-15 and PD-1 checkpoint blockade in combination with oncolytic Zika virus infection confers protection against immune-resistant gliomas.
  5. CD155 regulates tumor growth and susceptibility to T cell mediated killing in diffuse midline glioma.
  6. PET RANO 1.0 vs. RANO 2.0 criteria for trial eligibility in IDH-wildtype glioblastoma: a retrospective, comparative study.
  7. Prognostic and Predictive Effect of Age in Molecularly Defined Lower-Grade Gliomas.
  8. Druggable genome CRISPRi screen in hydrogels reveals regulators of cortactin-driven actin remodeling promoting glioblastoma invasion.
  1. Neuro Oncol. 2026 Aug 10. pii: noag185. [Epub ahead of print]
    Potent anti-tumor preclinical efficacy of B7-H3 CAR-T cells in H3G34-mutant, Diffuse Hemispheric Glioma.
    David Akhavan, Monika Yadav, Siddharth Subham, John Jeppson, Omar Tinoco, Scott Chin, Nadine Santana-Magal, Jacqueline Babai, John Szarejko, Garrett Gibson, Kirill Sabitov, Daniel B Zamler, G Doug Myers, Brooke L Fridley, Stefan H Bossmann, Kalyani Pyaram, Viveka Nand Yadav.
       BACKGROUND: Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a highly aggressive and fatal pediatric brain tumor, with a median survival of only ∼18 months and no effective targeted therapies. While CAR T cell therapy has shown success in B-cell leukemia and promise in other pediatric CNS tumors, it has not yet been evaluated explicitly in preclinical or clinical models of DHG. B7-H3 (CD276), a tumor-associated antigen overexpressed in pediatric brain tumors, represents a promising target for immunotherapeutic intervention in DHG. Here, we present the first preclinical evaluation of B7-H3-directed CAR T cell therapy in DHG.
    METHODS: We evaluated B7-H3 expression in specimens from DHG patients and patient-derived cell lines. Two B7-H3-targeted CAR constructs were generated and evaluated for antigen-specific activation, cytokine production, exhaustion, and cytotoxicity in vitro. Therapeutic efficacy was assessed in multiple orthotopic DHG xenograft models, followed by multiplex immunofluorescence and serum cytokine profiling.
    RESULTS: B7-H3 was highly expressed in DHG tumors and cell lines, but at minimal levels in normal brain tissue. B7-H3 CAR T cells demonstrated potent, antigen-specific cytotoxicity against DHG cells, with negligible activity against B7-H3-knockout DHG cells. In vivo, the intratumoral administration of B7-H3 CAR T cells led to significant tumor regression and a substantial extension of survival in three DHG mouse models, with durable tumor eradication.
    CONCLUSION: This study provides preclinical evidence supporting B7-H3 CAR T cell therapy as a highly effective immunotherapeutic strategy for DHG. Our findings support B7-H3 as a compelling immunotherapeutic target for DHG, laying the groundwork for clinical translation.
    Keywords:  B7-H3; CAR T cells; DHG; H3G34-mutant; Immunotherapy; Pediatric High-Grade Gliomas
    DOI:  https://doi.org/10.1093/neuonc/noag185
  2. Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2537768123
    Histone H3K27M variants determine myeloid subset dependencies and immune reprogramming in diffuse midline glioma.
    Montserrat Puigdelloses Vallcorba, Kavita Rawat, Nishant Soni, Angela DiMauro, Jacqueline D Chu, Wes Thomason, Glaucia C Furtado, Maya Strahl, Junyan Wu, Tanvi Joshi, Angelo Angione, Gonzalo Piñero, Oren J Becher, James L Ross, Alexander M Tsankov, Sergio A Lira, Dolores Hambardzumyan.
      Diffuse midline gliomas (DMGs) are highly aggressive, WHO grade 4 glial tumors that arise in midline central nervous system structures and are defined by K27M mutations in histone H3 genes. These K27M mutations shape intratumoral myeloid cell composition in DMG. In H3.1K27M DMGs, genetic ablation of monocyte recruitment reshapes the tumor microenvironment (TME) by reducing monocyte-derived macrophages (MDMs) and increasing microglia and neutrophil presence, with overall survival remaining unchanged, indicating compensatory myeloid remodeling is occurring. Here, by using CRISPR/Cas9-based genome editing, we generated a mouse model deficient for CCR1/CCR2/CCR3/CCR5 (Δ1235). Using this strain, we effectively abolished monocyte and MDM infiltration and reversed compensatory recruitment of CCR1+ neutrophils. Abolishing MDMs in tumors skewed remaining neutrophils and microglia toward a homeostatic state, reduced expression of immune checkpoint molecules on T cells, and extended the survival of H3.1K27M DMG-bearing mice. In contrast, H3.3K27M DMG showed independence from MDM recruitment, suggesting reliance on other TME-driven signaling. Last, H3.1K27M DMGs exhibited reduced microglia presence and a dose-dependent increase in MDM infiltration postirradiation. MDM depletion did not further enhance radiation efficacy, potentially due to compensatory recruitment of classical neutrophils. Collectively, these data reveal histone mutation-specific myeloid dependencies in DMG, highlighting MDM-independent mechanisms in H3.3K27M tumors and MDM-dependent pathways in H3.1K27M tumors.
    Keywords:  Glioma; microglia; monocyte; neutrophil; pediatric
    DOI:  https://doi.org/10.1073/pnas.2537768123
  3. Sci Rep. 2026 08 11. pii: 24908. [Epub ahead of print]16(1):
    Shifting AAV9 tropism by binding moiety insertion enhances transduction of tumor cell lines and human glioblastoma explants.
    Claire Rothschild-Gronau, Philipp Borchert, Marco T Radukic, Lucas Haverkamp, Roland Coras, Matthias Simon, Kristian M Müller.
      Tumor-specific targeting remains a major obstacle for the development of precision cancer therapies. For several tumors and specifically glioblastoma (GBM), an aggressive brain tumor with poor prognosis, more effective treatments are urgently needed. Recombinant adeno-associated viruses (rAAVs), with their established clinical utility and mutational capsid plasticity, offer a promising platform for targeted delivery. We engineered and evaluated modified AAV capsids derived from the established AAV2 with HSPG-tropism knockdown and two less-characterized, tropism-reduced AAV9 variants. The epidermal growth factor receptor (EGFR), a tumor marker often overexpressed in GBM, was targeted by inserting an affibody (ZEGFR:1907). Also chlorotoxin (CLTX) was inserted, a peptide from scorpion venom reported to bind GBM. Transduction efficiencies were initially assessed with established cell lines (A431, HeLa, U251MG, MCF7). Affibody-displaying capsids exhibited EGFR-dependent transduction, with AAV9-affibody variants surpassing AAV9 wild-type. Several affibody-displaying capsids also transduced patient-derived GBM explants, as confirmed by fluorescence microscopy. These findings highlight the potential of retargeting AAV9 variants and the use of human surgical tissue samples for the initial evaluation of newly designed AAV capsids.
    Keywords:  Capsid modification; Glioblastoma; Recombinant adeno-associated virus; Redirection; Tropism knock-out
    DOI:  https://doi.org/10.1038/s41598-026-62481-8
  4. Neuro Oncol. 2026 Aug 08. pii: noag186. [Epub ahead of print]
    Siglec-15 and PD-1 checkpoint blockade in combination with oncolytic Zika virus infection confers protection against immune-resistant gliomas.
    Ashwani Kesarwani, Amber Neil Griffith, Sonam Verma, Tong Hu, Fei Shu, Amanda De Andrade Costa, Yuping Derek Li, Mridu Kanga, Brett H Herzog, David G DeNardo, Mai T Dang, Jingqin Luo, Pei- Yong-Shi, Xuping Xie, Jun Wang, Lieping Chen, Albert Kim, Peggy Kendall, Michael S Diamond, Milan G Chheda.
       BACKGROUND: : The glioblastoma (GBM) immunosuppressive tumor microenvironment is a clinical challenge. Oncolytic Zika virus (ZIKV) has emerged as a promising therapy, targeting treatment-resistant glioma stem cells, stimulating CD8+ T-cell-mediated immunity and extends survival in preclinical models but myeloid cell-driven immunosuppression persists. An antagonist of Siglec-15, a myeloid immune checkpoint molecule, is in a phase II trial for non-small cell lung cancer, but its role in CNS malignancies remains unclear.
    METHODS: : We evaluated Siglec-15 expression in human GBM samples using flow cytometry, mass cytometry, and immunofluorescence, as well as a public database. Using syngeneic glioma models, we tested a blocking antibody against Siglec-15, and Siglec-15 knock out mice, alongside ZIKV and anti-PD-1 therapies. We performed survival studies and analyzed immune responses, T-cell proliferation and phagocytosis, and tumor rechallenge.
    RESULTS: : Siglec-15 was expressed by human GBM myeloid (16-22%) and tumor (18-19%) cells, and higher expression was associated with shorter survival. In CT2A-bearing mice, ZIKV + anti-Siglec-15 increased long-term survival to 60% (vs. 40% with ZIKV alone), rising to 83% with anti-PD-1 treatment. Triple therapy in SB28 bearing mice yielded 76% long-term survivor rate with 1.7-fold higher CD8+ T-cell activation. Rechallenged mice showed 11-fold expansion of brain resident/effector memory CD8+ T-cells and 80% survival. Siglec-15 loss on myeloid cells enhanced phagocytosis (CT2A: 25%; SB28: 7%) and T-cell responses (activation: 81%; proliferation: 86.8%).
    CONCLUSION: : Targeting Siglec-15, combined with PD-1 blockade and ZIKV overcomes myeloid immunosuppression and enhances T-cell activation in GBM, promoting durable anti-tumor immunity. These findings support further investigation of this combination therapy.
    Keywords:  CT2A; SB28; Siglec-15; Zika virus; glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noag186
  5. Neuro Oncol. 2026 Aug 10. pii: noag178. [Epub ahead of print]
    CD155 regulates tumor growth and susceptibility to T cell mediated killing in diffuse midline glioma.
    Theophilos Tzaridis, Ester Calvo Fernández, Tanja Eisemann, Angela Liou, Augusto Faria Andrade, Carlos A O de Biagi-Junior, Jennifer L Hope, Liam S Hewson, Michael McNicholas, Antonella De Cola, Manav Pathania, Oren J Becher, Nada Jabado, Jon D Larson, Suzanne J Baker, Andrea Califano, Anindya Bagchi, Matthew Gallitto, Cynthia Hawkins, Mariella G Filbin, Linda M Bradley, Peter D Adams, Jovana Pavisic, Robert J Wechsler-Reya.
       BACKGROUND: Diffuse midline glioma (DMG) is a devastating pediatric brain tumor with an unmet need for novel therapies. Immune checkpoint inhibitors have failed to prolong survival of DMG patients.
    METHODS: In this study, we screened for immune checkpoint molecules in DMG, evaluated immunological responses to checkpoint targeting by co-culture assays and depletion of immune cells in vivo, studied the effects of CD155 silencing by whole-transcriptome analyses and performed in vivo treatments with Thiostrepton.
    RESULTS: In human and murine DMG cells, as well as primary brain tumor samples, we identified CD155 as the most highly expressed immune checkpoint. When murine DMG cells were co-cultured with CD8+ T cells, silencing of CD155 led to a marked increase in T cell-mediated killing. Strikingly, CD155-deficient DMG cells failed to grow in immunocompetent mice, and depletion of CD8+ T cells allowed these tumors to grow. CD155 also exerted cell-autonomous effects on tumor cells: silencing of CD155 led to induction of apoptosis of DMG cells and delayed tumor growth in immunodeficient mice. Transcriptomic analyses identified FOXM1 as a key target of CD155. Notably, FOXM1 silencing also led to reduced proliferation of DMG cells in vitro and in vivo. Finally, treatment of DMG-bearing mice with Thiostrepton, a FOXM1-targeting agent, delayed tumor growth and prolonged survival.
    CONCLUSIONS: These studies demonstrate that CD155 regulates immune evasion and tumor growth in DMG, and suggest that targeting CD155 could be a valuable two-pronged therapeutic strategy for this disease.
    Keywords:  CD155; DMG; FOXM1; immune checkpoint; tumor growth
    DOI:  https://doi.org/10.1093/neuonc/noag178
  6. Neuro Oncol. 2026 Aug 14. pii: noag182. [Epub ahead of print]
    PET RANO 1.0 vs. RANO 2.0 criteria for trial eligibility in IDH-wildtype glioblastoma: a retrospective, comparative study.
    Katharina J Schmidbauer, Isabelle von Polenz, Jonas Reis, Lilian Wiegand, Maximilian J Mair, Thedora Aras, Jera Isakaj, Thomas Schabhüttl, Enio Barci, Robert Forbrig, Lena Kaiser, Rudolf A Werner, Florian Ringel, Stephan Schönecker, Veit M Stöcklein, Tobias Greve, Patrick Harter, Louisa von Baumgarten, Matthias Preusser, Nathalie L Albert.
       BACKGROUND: In glioblastoma studies, the presence of measurable disease is often required for trial eligibility. While response assessment according to RANO 2.0 relies on MRI, the recently introduced PET RANO 1.0 criteria allow standardized evaluation based on amino acid PET. This study compares the frequency of measurable disease according to PET RANO 1.0 vs. RANO 2.0 criteria at key enrollment timepoints of clinical trials.
    METHODS: In this retrospective, single-center study, we included patients with IDH-wildtype glioblastoma who underwent both [¹⁸F]FET PET and MRI, after standard first-line radiotherapy (time-point T0) (defined per RANO 2.0) or at first progression (time-point T1). Two independent raters evaluated measurable disease using PET RANO 1.0 and RANO 2.0 criteria. Further, tumor size, target lesions and tracer uptake metrics were analyzed.
    RESULTS: In total 322 patients were included, 112 at T0 (median age: 59 years, IQR 54-69), and 210 at T1 (median age: 59, IQR 53-67). On MRI, measurable disease was identified in 57/112 patients (50.9%) at T0 and in 137/210 patients (65.2%) at T1 (median sum of products of cross-sectional diameters: 143mm2; 187mm2). On PET, significantly more cases with measurable disease were detected: 102/112 patients, (91.1%) at T0 and 201/210 patients (95.7%) at T1 (median volumes: 9.86cm³; 14.3cm³) (p = 0.001).
    CONCLUSION: PET RANO 1.0 detects a substantially larger subset of patients with measurable disease compared to RANO 2.0. These findings warrant prospective validation of PET-based measurable disease as an inclusion criterion for clinical trials in IDH-wildtype glioblastoma, with the potential to broaden trial eligibility.
    Keywords:   IDH-wildtype glioblastoma; PET RANO 1.0; RANO 2.0; response assessment
    DOI:  https://doi.org/10.1093/neuonc/noag182
  7. J Clin Oncol. 2026 Aug 12. JCO2501846
    Prognostic and Predictive Effect of Age in Molecularly Defined Lower-Grade Gliomas.
    Connor J Kinslow, Giuseppe Minniti, Paul D Brown, Michael A Vogelbaum, Karla V Ballman, Ann Mercurio, Markus D Siegelin, Emre Kocakavuk, Kyle Tuohy, Alireza Mansouri, Mehdi Touat, François Ducray, Caroline Dehais, Angelo Dipasquale, Matteo Simonelli, David M DeStephano, Jack Grinband, James B Yu, Henry Walch, Mitchell I Parker, Igor Shuryak, Soumyajit Roy, Shawn L Hervey-Jumper, Matthew Gallitto, David P Horowitz, Guy M McKhann, Michael B Sisti, Jeffrey N Bruce, Peter Canoll, Quinn T Ostrom, Alfred I Neugut, Luke R G Pike, Fabio M Iwamoto, Simon K Cheng, Lisa A Kachnic, Minesh P Mehta, Tony J C Wang.
       PURPOSE: Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era.
    METHODS: The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 (IDH1/2) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database).
    RESULTS: We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH-mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], Pinteraction < .001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/-10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH-mutant glioma.
    CONCLUSION: In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.
    DOI:  https://doi.org/10.1200/JCO-25-01846
  8. JCI Insight. 2026 Aug 10. pii: e196484. [Epub ahead of print]11(15):
    Druggable genome CRISPRi screen in hydrogels reveals regulators of cortactin-driven actin remodeling promoting glioblastoma invasion.
    Mufeng Hu, Anna Weldy, Isabella M Lovalvo, Erin A Akins, Saket Jain, Alexander Chang, Ankita Sati, Meeki Lad, Austin Lui, Akhil Rajidi, Ameya Kothekar, Erika A Ding, Juan A Oses Prieto, Pablo Estevez, Alma L Burlingame, Sanjay Kumar, Manish K Aghi.
      To identify therapeutic targets limiting glioblastoma invasion, we applied druggable genome CRISPRi screens and multiomic analysis to patient-derived glioblastoma cells in micro-dissectible biomimetic 3D hydrogels that permitted separation and analysis of core versus invasive fractions. Of 2,550 genes screened, 12 encoded druggable targets whose suppression limited invasion, of which AURKB (encoding aurora kinase B) and ACP1 (encoding low molecular weight protein tyrosine phosphatase, LMW-PTP) were validated in neurosphere assays and in vivo. Proximity labeling identified cortactin as a link between LMW-PTP and aurora B, and we observed that cortactin underwent serine phosphorylation by aurora B and tyrosine dephosphorylation by LMW-PTP. Targeting ACP1 or AURKB via CRISPRi or inhibitors in culture and in vivo shifted the cortactin phosphorylation balance in glioblastoma, reducing levels of cortactin and the actin-related protein 2/3 (Arp2/3) complex that mediates cortactin-induced actin stabilization, thereby reducing actin-cortactin-Arp2/3 colocalization and subsequent actin polymerization. AURKB or ACP1 targeting shifted actin from cytoplasm to the nucleus, reducing mesenchymal gene expression. Biophysical analysis implicated AURKB in glioblastoma cell adhesion and stiffness needed for initial migration and ACP1 in mechanical stress resistance required for later migration. These findings revealed a targetable axis balancing kinase and phosphatase activities to regulate actin polymerization during glioblastoma invasion.
    Keywords:  Brain cancer; Cell biology; Cell migration/adhesion; Drug screens; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.196484
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