RARE DISEASE
Diffuse intrinsic pontine glioma
Diffuse intrinsic pontine glioma
Diffuse intrinsic pontine glioma
Synonyms: DIPG
Synonyms: DIPG
Synonyms: DIPG
Drug discovery
5
drugs
With orphan designations
Overview
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor arising in the pons, characterized by diffuse infiltration of glial cells and molecular drivers like H3K27M histone mutations. Diagnosis relies on clinical presentation and MRI findings, with median survival of 8–12 months despite radiotherapy providing temporary symptom relief. No curative therapies exist due to its critical location and resistance to conventional treatments [1][4][11].
Therapies
Radiotherapy: Standard 54–60 Gy fractionated radiation improves symptoms transiently [3][5][16].
Clinical trials: Epigenetic modifiers (e.g., histone deacetylase inhibitors), immunotherapy, and targeted agents (e.g., nimotuzumab) under investigation [7][8][18].
Palliative care: Steroids for edema management and supportive therapies dominate post-progression care [1][12].
Categories: rare neoplastic diseases, rare neurological diseases
Research Papers
1,889 drug discovery papers about Diffuse intrinsic pontine glioma, with 4 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
1,889 drug discovery papers about Diffuse intrinsic pontine glioma, with 4 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-30 | Synergistic antitumor effect of HMGB2 targeting combined with MDM2 inhibitor in diffuse intrinsic pontine glioma therapy.
Diffuse intrinsic pontine glioma (DIPG) is a brain malignancy in children with a dismal prognosis. The high mobility group box 2 (HMGB2) is a member of the HMGB family of chromatin-associated proteins, and is identified as a potential oncogene in various cancers. However, the effects of HMGB2 in DIPG remains unclear. In this study, we observed aberrant expression of HMGB2 in multiple cancer types, with its expression level being negatively correlated with clinical outcomes across pan-cancers. High expression of HMGB2 was determined in DIPG cells, but not in primary brainstem neural progenitor cells (PPCs). Knockdown of HMGB2 significantly inhibited the DIPG cell proliferation and induced cell apoptosis. Intriguingly, bulk RNA sequencing revealed that inhibition of HMGB2 upregulated p53 protein expression and enhanced the activity of p53-p21 axis. Combining HMGB2 inhibitor with a p53-MDM2 inhibitor RG7388 resulted in a synergistic suppression of DIPG cell growth and promoted cell apoptosis by activating the tumor suppressor p53 and p21 expressions in vitro. The animal studies demonstrated that the combination treatment significantly inhibited tumor growth and prolonged the survival of mice bearing orthotopic DIPG tumors. These findings demonstrate that HMGB2 acts as an oncogene in DIPG tumorigenesis, and targeting HMGB2 combined with MDM2 inhibitor provides a novel preclinical basis for the development of DIPG therapeutic strategies.
2026-09-22 | Disruption of lamina-associated genome organization activates neuronal gene programs in H3.3K27M DIPG
Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor frequently driven by a histone H3 mutation that substitutes lysine 27 with methionine (H3K27M). While H3K27M is known to cause a global depletion of the repressive histone mark H3K27me3, how this epigenetic disruption contributes to oncogenic transcriptional reprogramming remains incompletely understood. Here, we show that H3.3K27M DIPG cells exhibit widespread disruption of lamina-associated domain (LAD) organization across primary tumors and patient-derived cell lines. H3.3K27M was enriched at genomic regions that lost lamina association, which acquired increased H3K27ac and showed activation of neuronal and oncogenic gene programs. Notably, LAD loss was more strongly associated with transcriptional activation than H3K27me3 depletion, linking altered LAD organization to the transcriptional consequences of H3.3K27M. Finally, expression of H3.3K27M in human embryonic stem cell-derived neural precursor cells (NPCs) was sufficient to induce LAD remodeling, predominantly through loss of lamina association, leading to activation of neuronal gene programs. Together, these findings identify disruption of lamina-associated genome architecture as a key mechanism by which the H3.3K27M oncohistone drives oncogenic transcriptional reprogramming in DIPG.
2026-09-17 | CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas.
Pediatric-type diffuse high-grade gliomas (pHGG) are aggressive, largely incurable malignancies often characterized by PI3K/AKT pathway activation. This study investigated whether the PI3K inhibitor inavolisib and the AKT inhibitor ipatasertib could achieve therapeutic concentrations in the central nervous system (CNS) and demonstrate efficacy against PIK3CA-mutated pHGG. A panel of 12 pHGG cell lines with diverse PI3K/AKT genetic aberrations was screened for sensitivity to inavolisib and ipatasertib. Pharmacokinetic (PK) modeling was performed in mice to determine brain-to-plasma exposure ratios following oral administration (50 mg/kg inavolisib and 100 mg/kg ipatasertib). Finally, the in vivo efficacy of both inhibitors was evaluated using intracranial PIK3CA-mutated pHGG xenograft models, with survival and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) levels as primary endpoints. All 12 cell lines exhibited PI3K/AKT alterations. The PIK3CA H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC50 = 0.016 µM for inavolisib; 0.52 µM for ipatasertib). PK modeling revealed geometric mean brain-to-plasma ratios of 0.07 for inavolisib and 0.20 for ipatasertib, with model-predicted maximum brain concentrations of 0.69 µM and 0.93 µM, respectively. In vivo, inavolisib significantly extended survival (P = 0.0070) and increased CSF ctDNA release (P = 0.0317). In contrast, ipatasertib did not demonstrate significant in vivo activity. These findings highlight the therapeutic potential of inavolisib for treating PIK3CA-mutated pHGG. Despite the blood-brain barrier, inavolisib achieved sufficient CNS exposure to prolong survival in preclinical models, whereas ipatasertib efficacy did not translate from in vitro to in vivo settings.
2026-09-03 | Diffuse intrinsic pontine glioma in the era of H3 K27-altered diffuse midline glioma.
Diffuse intrinsic pontine glioma (DIPG), most commonly corresponding pathologically to diffuse midline glioma (DMG), H3 K27-altered, remains an overwhelmingly lethal pediatric brainstem malignancy, with median overall survival of approximately 11 months. We critically synthesized evidence identified through a structured search to December 31, 2025, supplemented by targeted updates of regulatory documents, clinical-trial records, and pivotal or practice-relevant publications through July 2026. We summarize epidemiology and the clinico-radiographic syndrome; examine the transition toward integrated molecular classification supported by stereotactic biopsy, with liquid biopsy emerging as a complementary tool; and distill core biology centered on PRC2 inhibition, loss of H3K27 trimethylation, developmental cell states, neuron-glioma interactions, and recurrent co-alterations involving TP53/PPM1D, ACVR1, PDGFRA, and PI3K/MAPK pathways. Radiotherapy remains the only modality with reproducible, albeit transient, clinical benefit; evidence supports hypofractionation in selected patients and reirradiation for carefully selected patients at recurrence. We appraise why cytotoxic chemotherapy and most targeted or epigenetic approaches have failed to deliver reproducible benefit, while highlighting early signals from CAR T-cell therapy, neoantigen vaccination, oncolytic virotherapy, and locoregional or ultrasound-enabled delivery. We also examine dordaviprone, the first systemic therapy to receive FDA accelerated approval for H3 K27M-mutant DMG with progressive disease following prior therapy, while emphasizing that the regulatory efficacy population excluded DIPG and therefore does not establish efficacy in classic pediatric pontine disease. Trial design must also explicitly separate anatomic phenotype from molecular taxonomy. Priorities include molecularly stratified enrollment, pharmacokinetically verified brainstem exposure, rational combinations, and endpoints integrating survival, neurologic function, and quality of life.
2026-09-01 | Integrated Transcriptomic and CRISPR Dependency Analysis Prioritizes a CDK1–AURKB Mitotic Vulnerability Axis in Diffuse Intrinsic Pontine Glioma
Abstract Diffuse intrinsic pontine glioma (DIPG), now classified within diffuse midline glioma, H3K27-altered, remains a lethal pediatric brainstem tumor with limited therapeutic options. Here, we integrated public DIPG transcriptomic datasets, protein–protein interaction modeling, functional enrichment, immune deconvolution, survival analysis, and DepMap CRISPR dependency data to nominate candidate mitotic vulnerabilities. Differential expression analysis comparing 27 DIPG tumors with 6 brainstem low-grade glioma comparator samples identified a proliferative transcriptional program enriched for chromosome segregation, nuclear division, and cell-cycle pathways. Network analysis prioritized a compact mitotic hub module containing CDK1, AURKB, TOP2A, CDC20, CDCA8, and related G2/M regulators. CIBERSORT analysis of an independent DIPG cohort inferred low cytotoxic T-cell signal, consistent with an immune-cold phenotype, although immune-cell fractions require orthogonal validation. Survival analysis showed that neither inferred immune scores nor a composite mitotic hub score significantly stratified overall survival. DepMap CRISPR gene-effect data nominated CDK1, AURKB, TOP2A, and BIRC5 as candidate dependencies across brain tumor models. These findings provide a computational framework for prioritizing mitotic vulnerabilities in DIPG and support experimental validation in disease-relevant models.
cell therapies
2026-09-01 | A CAR-T Tonic Signaling Code Predicts Anti-Tumor Efficacy in Diffuse Midline Glioma.
Diffuse middle glioma (DMG or DIPG) is a fatal pediatric brain tumor. Although chimeric antigen receptor (CAR) T-cell therapy shows promise, clinical outcomes remain inconsistent due to premature exhaustion, underscoring a critical need to improve CAR-T persistence. A major barrier to CAR-T efficacy is antigen-independent tonic signaling, yet the extent to which tonic signaling shapes CAR-T durability and clinical outcomes, particularly in DMG, remains incompletely defined. Using a clinically investigated B7-H3 MGA271-based CAR as a reference platform, we generated alternative B7-H3 CARs incorporating either a human codon-optimized 376.96 (B7H3.BC) or Hu8H9 scFv antigen binding domain to systematically assess scFv-dependent effects on tonic signaling and therapeutic efficacy. CAR-T cells were evaluated using integrated in vitro and in vivo functional assays, alongside multi-omics profiling and computational modeling. We further derived a tonic signaling-associated gene signature and evaluated its predictive performance across independent clinical datasets. B7H3.BC CAR-T cells exhibit markedly restrained tonic signaling compared with MGA271- and Hu8H9-based counterparts, accompanied by superior antitumor activity and enhanced persistence across patient-derived DMG cells. Integrated multi-omics and single-cell profiling further identified a tonic signaling-associated gene signature that outperforms conventional T-cell exhaustion signatures in predicting therapeutic efficacy across multiple clinical trials, including DMG and other tumors. Our findings establish that scFv-dependent modulation of tonic signaling critically governs CAR-T persistence and antitumor efficacy in DMG. By linking CAR design to transcriptional and epigenetic programs, our study provides a principle-based and predictive framework to inform rational CAR engineering and improve therapeutic outcomes.
2026-08-08 | CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13Rα2, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.
2026-08-07 | Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
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. 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. 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. 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.
2026-07-01 | Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial.
Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a manufacturing technique has been developed to target these intracellular TAAs using autologous, nongenetically engineered T cells. Here we therefore conducted ReMIND, an open-label, phase 1 adaptive dose-finding study to determine the safety/feasibility of autologous, systemically administered trivalent T cells targeting WT1, PRAME and survivin in children with CNS tumors. Eligible patients had newly diagnosed diffuse intrinsic pontine glioma without lymphodepletion (arm A, n = 16 enrolled, n = 11 infused) and relapsed/recurrent nonbrainstem CNS malignancies without (arm B, n = 28 enrolled, n = 18 infused) or with (arm C, n = 7 enrolled, n = 4 infused) lymphodepletion. Primary end points were safety, feasibility and maximum tolerated dose determination; secondary end points included preliminary efficacy and immunobiological correlates, including in vivo TAA-T persistence and systemic immune activation. Dose level 3 (8 × 107 cells per m2 per dose) was determined as the maximum tolerated dose. Treatment was well tolerated with fatigue and headache being the most common adverse events, although two possibly related serious adverse events of tumor swelling occurred. One grade 5 event in a patient with diffuse intrinsic pontine glioma with hydrocephalus, tumor edema and respiratory failure was categorized as a dose-limiting toxicity. Median overall survival for arm A was 13.7 months from diagnosis (range, 6.2-32.0) and median progression-free survival for arms B/C was 5.0 months from infusion (range, 0.5-51.6). Three patients in arms B/C are alive without disease at 31.8, 41.2 and 51.6 months without further treatment, including one complete response. This trial met safety/feasibility primary end points with some preliminary signals of efficacy. ClinicalTrials.gov registration: NCT03652545 .
antibodies
2026-09-22 | Integrated multi-omics identifies lineage-dependent myeloid cells recruitment and the APP-CD74 axis as an immunoregulatory target in pediatric high-grade glioma.
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with limited treatment options. Emerging evidence indicates infiltration of tumor-associated macrophages (TAMs) within tumor sites, accompanied by an immunosuppressive tumor microenvironment (TME). However, the mechanisms underlying macrophage recruitment and communication between TAMs and other cellular compartments within brain tumors remain poorly understood. Bulk RNA sequencing of 26 DIPG autopsy specimens with matched normal brain tissue, single-cell RNA sequencing data from eight DIPG patients integrated with public pediatric high-grade glioma (pHGG) datasets, and in vitro transwell and flow cytometry assays collectively indicated that DIPG tumors actively recruit monocytes through chemokine-mediated mechanisms. The chemokine expression of tumor cells is driven by a mesenchymal-like (MES-like) lineage state rather than histone mutations, as evidenced by significant correlation between MES-like lineage scores and chemokine expression scores across 46 pHGG cell lines. CellChat analysis predicted APP-CD74 signaling as a prominent tumor cell-TAM interaction pathway, supported by immunofluorescence validation. Notably, APP expression was significantly reduced in DIPG tumor tissues compared with normal brain tissue at both the RNA and protein levels. Recombinant APP stimulation of THP-1-derived macrophages induced a robust proinflammatory response, including upregulation of M1-like markers, enrichment of interferon-related pathways, and elevated secretion of inflammatory cytokines. Collectively, these findings suggest that reduced APP expression in tumor may contribute to a non-inflammatory TAM phenotype and an immunosuppressive microenvironment. Furthermore, protein modeling and docking analyses identified the APP-CD74 binding interface, providing a structural basis for therapeutic targeting.
2026-06-30 | Pediatric Brain Tumor Consortium phase 1 study of CD40 agonist sotigalimab in pediatric and young adult patients with recurrent CNS tumors and newly-diagnosed DIPG.
The PBTC-051 study is the first pediatric evaluation of a CD40 agonist and assessed the safety, pharmacokinetics, and preliminary efficacy of sotigalimab in children and young adults with recurrent or progressive malignant central nervous system (CNS) tumors (stratum 1) and post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) (stratum 2). This prospective phase 1 study conducted by the Pediatric Brain Tumor Consortium evaluated sotigalimab using a 3+3 design for dose escalation. Immune pharmacodynamics were assessed with RNA transcript analysis, T cell receptor sequencing, and cytokine profiling. 31 eligible patients were enrolled (stratum 1: 20, stratum 2: 11). The stratum 1 recommended phase 2 dose was 0.6 mg/kg every 3 weeks; the stratum 2 maximum tolerated dose was 0.3 mg/kg every 3 weeks. Five patients had dose-limiting toxicities. No patients had an objective response. For stratum 1, 6-month and 12-month progression-free survivals (PFS) were 13.3% (standard error [SE], 8.1%) and 6.7% (SE, 6.2%), respectively; for stratum 2, 6-month PFS and overall survival were 31.2% (SE, 14.8%) and 44.4% (SE, 16.6%), respectively. At all dose levels, the maximum serum concentration was reached at the end of infusion; no drug accumulation was detected. More than 40% of patients developed anti-drug antibodies. Signaling pathways associated with activated antigen presenting cells and T cells were enriched in patients with higher PFS, while increased loss of heterozygosity was noted in patients with lower PFS. Sotigalimab was well-tolerated in pediatric patients with recurrent or progressive CNS tumors and post-radiation pre-progression DIPG.
2026-06-29 | Tumor-Targeted pan-RAS Inhibition as a Novel Biologic Therapy for Diffuse Midline Glioma.
Pediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer-related deaths. Those arising in the midline harboring a lysine to methionine substitution at position 27 in histone 3 (H3K27M), termed diffuse midline glioma (or DIPG when occurring in the pons), are particularly deadly and in need of additional therapeutic options. Our group and others have found upregulation of the RAS/MAPK pathway across HGGs, including DIPG; however, RAS is notoriously difficult to target therapeutically, with no approved drugs that can target non-mutant RAS proteins. We leveraged a pan-RAS-cleaving biologic (RRSP-DTB) to define RAS dependency in DIPG and employed proteomic profiling of patient-derived tumors to identify enriched cell-surface receptors for tumor-selective targeting. RRSP was re-engineered to engage the lead candidate receptor, tumor endothelial marker 8 (TEM8/ANTXR1), generating a targeted RAS-degrading biologic evaluated in vitro and in orthotopic DIPG xenograft models. Pan-RAS cleavage revealed DIPG to be critically dependent on RAS/MAPK signaling compared to other RAS/MAPK HGGs. Targeting RRSP to TEM8 enabled efficient intracellular delivery, resulting in complete RAS ablation and apoptotic cell death in patient-derived DIPG cells at low picomolar concentrations. In vivo, intracerebroventricular delivery reduced leptomeningeal disease burden (p = 0.04), while convection-enhanced delivery extended survival in orthotopic DIPG models (median survival 68 vs. 57 days; p = 0.016). We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.
2026-06-23 | ID #315 The Impact of Bevacizumab on Quality of Life in Diffuse Intrinsic Pontine Glioma (DIPG) Patients: A Systematic Review
Abstract Background Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive pediatric brain tumor, typically resistant to treatment. Despite advancements in therapeutic approaches like radiation, prognosis remains poor. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has shown potential in alleviating tumor-related symptoms but its effect on the quality of life (QoL) of DIPG patients is still uncertain. Methods A systematic review was conducted using databases such as PubMed, Google Scholar, Science Direct, and EBSCOhost, examining studies published in the last ten years. The inclusion criteria focused on studies assessing the impact of Bevacizumab on QoL for children with DIPG. Studies using quality of life assessment tools such as the Pediatric Quality of Life Inventory (PedsQL) were included. Results Five studies were included in the review, and the findings suggested temporary improvements in cognitive and physical functioning during treatment with Bevacizumab. Common side effects included lymphopenia and thrombocytopenia. However, long-term survival outcomes remained limited, with median survival ranging from 13.8 to 14 months. Conclusion Bevacizumab may provide short-term symptomatic relief in DIPG patients, particularly in cognitive and physical domains, but its limited impact on long-term survival and overall QoL highlights the need for further research into targeted therapies and personalized treatments. Future studies should focus on improving survival outcomes and refining combination therapies to enhance patient well-being. 1. 1. Hummel TR, Salloum R, Rachid Drissi, Kumar S, Sobo M, Goldman S, et al. A pilot study of bevacizumab- based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. Journal of neuro-oncology. 2015 Dec 1;127(1):53–61. 2. Jansen MH, Veldhuijzen van Zanten SEM, van Vuurden DG, Huisman MC, Vugts DJ, Hoekstra OS, et al. Molecular Drug Imaging:89Zr- Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma. Journal of Nuclear Medicine. 2016 Oct 20;58(5):711–6. 3. Crotty EE, Leary SES, Geyer JR, Olson JM, Millard NE, Sato AA, et al. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. Journal of Neuro-Oncology. 2020 Jun 16;148(3):607–17. 4. El-Khouly FE, Sophie, Marc, Bakker DP, Aliaga ES, Hendrikse NH, et al. A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma. Journal of Neuro- Oncology. 2021 May 7;153(2):263–71. 5. Honda M, Fukuoka K, Tanami Y, Kurihara J, Koh K. Bevacizumab for the early clinical progression of diffuse intrinsic pontine glioma. Pediatrics International [Internet]. 2023 Jan [cited 2026 Jan 11];65(1).
2026-04-03 | Abstract 644: Evaluating GD2-targeting antibody-drug conjugates for DIPG using human organoid-based preclinical platforms.
Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with a median survival of less than 12 months. Although the recent FDA accelerated approval of ONC201 offers a long-awaited sense of progress for the DIPG/DMG community, the central therapeutic problem remains far from solved. The frequent presence of H3K27M mutations in DIPG is associated with elevated expression of GD2, a clinically actionable surface antigen. GD2-directed CAR-T therapies have shown encouraging early activity in DIPG. However, challenges such as antigen heterogeneity, inherent manufacturing lead time, and risks of neurotoxicity remain. Antibody-drug conjugates (ADCs) offer a more controllable, off-the-shelf therapeutic approach that could overcome these limitations, yet their potential in DIPG remains unexplored. To evaluate the efficacy, resistance, and safety of GD2-targeting ADCs, we employed two complementary human-derived organoid platforms. First, DIPG models were generated using NanoGlio, a high-throughput nanoliter-volume droplet 3D organoid system. Second, we established a co-culture model with DIPG NanoGlio and iPSC-derived brain organoids to assess neurotoxicity. We successfully generated NanoGlio derived from 9 DIPG models reflecting the key genetic alterations typically identified in DIPG, including mutations in H3.3 (H3F3A) or H3.1 (HIST1H3B). We assessed the expression of GD2 by flow cytometry and 3D-Fluorescence Antibody Cell Tracking (3D-FACT) and observed widely variable GD2 expression across DIPG models. We tested M3554, a first-in-class clinical-stage anti-GD2 ADC conjugated to exatecan, a topoisomerase I inhibitor, in these models. M3554 exhibited potent cytotoxicity across DIPG NanoGlios. Resistance profiling using its unconjugated payload, Exatecan, revealed that reduced ADC response was primarily driven by intrinsic payload resistance rather than low GD2 expression. DIPG models with very low GD2 expression, including SF7761 and SU-DIPG-IV, also responded strongly to M3554, consistent with a bystander killing effect. iPSC-derived brain organoids (GD2-negative) showed minimal toxicity with M3554, whereas equivalent doses of Exatecan induced extensive cell death. Future work will systematically evaluate GD2 ADC bystander effect via co-encapsulation of GD2+ and GD2- DIPG cells, and assess the efficacy and neurotoxicity of M3554 using our DIPG-brain co-culture model. Successful completion of this study will provide critical preclinical evidence supporting the assessment and use of GD2-targeting ADCs in DIPG treatment. Citation Format: Zhikun Wang, Emily Miller, Wei Huang, Satoru Kawakita, Lauren Vanderpool, Francisco Bustamante, Uijin Kim, Zhaohui Wang. Evaluating GD2-targeting antibody-drug conjugates for DIPG using human organoid-based preclinical platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 644.
gene therapies
2026-09-26 | Virotherapy for Spinal and Spinal Cord Tumors: Current Evidence and Future Perspectives.
Tumors of the spine and spinal cord, including primary and metastatic vertebral tumors, intramedullary gliomas, and refractory intradural lesions, are challenging to treat because curative local therapy is limited by the eloquent, nonregenerating neural tissue surrounding them. Oncolytic virotherapy may offer a rational alternative by combining tumor-selective oncolysis with the induction of systemic antitumor immunity, while sparing normal neural cells. This review summarizes the current field of oncolytic viruses, including adenovirus, herpes simplex virus, reovirus, and others, in the context of spinal and spinal cord tumors. Clinical data in the spine remain scarce; however, the rationale is based on histological evidence from sarcomas and other tumors, extensive glioma experience, including diffuse intrinsic pontine glioma, and preclinical activity in nerve sheath and meningioma models. We discuss the telomerase-specific oncolytic adenovirus OBP-301 and its derivatives, whose hTERT-driven replication provides histology-agnostic tumor selectivity, while sparing the telomerase-silent spinal cord. This telomerase dependence, however, limits activity against tumors that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, such as many osteosarcomas and some spinal cord astrocytomas. We also discuss delivery and safety within the confined spinal canal, combination strategies, and future directions, such as extracellular vesicle-mediated delivery and biomarker-guided patient selection. Although clinical translation to the spine will require dedicated preclinical and early-phase studies, virotherapy represents a promising, mechanistically grounded modality for these therapeutically challenging tumors.
2026-06-17 | Modeling diffuse midline glioma through triple-electrode in utero electroporation of the developing mouse pons.
The leading cause of brain cancer-related death in children is diffuse midline glioma (DMG). A particularly aggressive DMG subtype is pontine DMG (formerly diffuse intrinsic pontine glioma, DIPG), which is caused by the histone mutation H3.3K27M. Because of its diffuse growth and location in a critical brainstem structure, therapeutic options are limited, and pontine DMG is considered universally fatal. The lack of appropriate animal models has hindered our understanding of the developmental origins and progression of pontine DMG, which in turn has limited the development of effective therapeutics. To address this barrier, several labs have developed mouse in utero electroporation approaches to express canonical DMG mutant oncogenes in the developing pons. In this manuscript and accompanying protocol, we describe a modified in utero electroporation strategy to generate DMG tumors in the developing mouse pons. Our protocol incorporates a single plasmid construct that expresses canonical DMG oncogenes, eliminating the need to co-electroporate multiple plasmids. We also employ a triple-electrode configuration to precisely target neural progenitors lining the fourth ventricle, which give rise to cells in the pons. As the embryos continue to develop in utero and postnatally, they form large, diffuse brainstem tumors with molecular characteristics of pediatric pontine DMG, allowing us to model the formation and progression of this deadly pediatric brain cancer.
2026-02-18 | A Decade of Oncolytic Virotherapy in Pediatric Cancers: A Systematic Review of Safety, Immune Awakening, and Emerging Efficacy.
Oncolytic virotherapy employs genetically modified viruses to selectively lyse tumor cells while activating antitumor immune responses. In pediatric oncology, where outcomes for high-grade gliomas and refractory solid tumors remain poor, oncolytic viruses represent a promising therapeutic strategy. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, including searches of PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov for studies published between 2015 and 2025 that evaluated oncolytic virotherapy in patients aged 18 years or younger. Data on safety, efficacy, and immune-related outcomes were extracted, study quality was assessed using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool, and the certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Ten early-phase clinical trials involving 115 pediatric patients met the inclusion criteria. Investigated viral platforms included herpes simplex virus type 1 (G207, HSV1716), adenovirus (DNX-2401, ICOVIR-5, Ad-TD-nsIL12), T-VEC (HSV-1), poliovirus (PVSRIPO), Seneca Valley virus, and reovirus. Across studies, no treatment-related deaths or persistent grade 3 or higher toxicities were reported, and adverse events were generally mild and transient. Radiologic or clinical disease control rates ranged from 20% to 90%, with median overall survival between 11 and 18 months in selected central nervous system tumor cohorts. Translational analyses demonstrated increased CD8⁺ T-cell infiltration, upregulation of interferon-γ and interleukin-6 signaling pathways, and evidence of transient viral replication, supporting immune-mediated antitumor mechanisms. Overall risk of bias was moderate, while the certainty of evidence was rated as low for safety outcomes and very low for efficacy. These findings indicate that oncolytic virotherapy is safe, feasible, and biologically active in children with malignant brain and solid tumors, and that preliminary survival signals and consistent immune activation support further investigation through larger, multicenter randomized trials and combination strategies with radiotherapy or immune checkpoint inhibitors.
2026-01-28 | Tropism Profiling of Lentiviral Vector Pseudotypes in Diverse Brain Tumor Models.
Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants-VSV-GP, FuG-B2, and LCMV-GP-across diverse brain tumor cell lines including glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, and metastatic brain cancers. Results: VSV-GP and FuG-B2 pseudotypes significantly outperformed LCMV-GP across most tumor types. Both VSV-GP and FuG-B2 demonstrated high transduction efficiency in GBM and DIPG cells, though some cell lines displayed selective preferences for one pseudotype over the other. Medulloblastoma cells were challenging to transduce, with only VSV-GP achieving substantial efficacy. Metastatic brain cancers showed distinct tropism patterns: melanoma metastases were preferentially transduced by the FuG-B2 pseudotype, while lung metastases showed preference for the VSV-GP pseudotype. Conclusions: These findings suggest envelope protein selection should be tailored to specific brain tumor types. VSV-GP appears most suitable for medulloblastoma and lung metastases, FuG-B2 for melanoma metastases, and both for GBM and DIPG gene therapy applications. The study provides crucial guidance for translating lentiviral gene therapy to clinical applications, supporting personalized treatment strategies based on tumor-specific vector tropism profiles.
2025-12-09 | [Current Status and Future Perspectives of Clinical Trials for Diffuse Intrinsic Pontine Gliomas(DIPG)].
Diffuse intrinsic pontine glioma (DIPG) remains one of the most devastating pediatric central nervous system tumors, with a median survival of approximately 11 months despite decades of research. The identification of histone H3 K27M mutations marked a pivotal moment, leading to major advancements in understanding the molecular and epigenetic characteristics of these tumors. This discovery enabled molecular classification and provided a basis for the development of novel therapeutic strategies. In recent years, clinical trials have investigated molecular targeted agents and epigenetic modulators. Immunotherapeutic approaches, such as CAR-T cell therapy, have shown promising early results, whereas innovative drug delivery techniques, including convection-enhanced delivery and focused ultrasound, aim to overcome the challenges of the blood-brain barrier. Two major international registries, the International DIPG/DMG Registry (IDIPGR) and the European Society for Paediatric Oncology (SIOPE) DIPG/DMG Registry, play crucial roles in collecting comprehensive clinical data across multiple countries. The DIPG-2023 registry study was launched in Japan to collect prospective clinical, radiological, and molecular data systematically and to provide a high-quality external control cohort for future intervention trials. These collaborative efforts highlight a new era of DIPG/DMG research, offering cautious optimism for therapeutic progress in this historically refractory disease.
other
2026-06-09 | A RaPID Macrocyclic Peptide Inhibitor of ROR1/2 Strongly Reduces Proliferation of Diffuse Intrinsic Pontine Glioma Cells.
We report the de novo discovery of a cyclic peptide inhibitor of ROR1/2 from the RaPID (random nonstandard peptides integrated discovery) system. Multiple independent affinity selection campaigns converged on a highly conserved family of sequences exhibiting single-digit nanomolar binding affinities to ROR1. One peptide from this family containing three nonproteinogenic residues, including a key cyclic β-amino acid, displayed pronounced activity in cellular assays. Strikingly, this peptide induced potent growth inhibition across multiple Diffuse Intrinsic Pontine Glioma (DIPG) cell lines, whereas other family members had no measurable cellular effects. Mechanistic analysis revealed that the active peptide uniquely competes with Wnt5a, the endogenous ligand of ROR1, for receptor binding. To our knowledge, this report provides the first evidence implicating ROR1/2 as a viable therapeutic target in DIPG and establishes macrocyclic peptides as a promising modality for its pharmacological inhibition.
2026-05-24 | Phase 1/2 study of a WT1 peptide-dosing emulsion in pediatric patients with recurrent/refractory diffuse intrinsic pontine glioma, glioblastoma, or anaplastic astrocytoma.
The prognosis of pediatric patients with diffuse intrinsic pontine glioma (DIPG), glioblastoma, or anaplastic astrocytomas (AAs) is dismal. This first-in-child phase 1/2 study examined the safety and efficacy of a Wilms' tumor gene 1 (WT1) peptide vaccine, along with the associations of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) frequency/count with clinical outcomes. Patients (<20 years) were intradermally injected with the vaccine. Among all patients (N = 18; median age: 8.9 years), 11, 5, and 2 had DIPG, glioblastoma, and AAs, respectively. In Phase 1 (n = 4), 3.5 mg was determined for use in Phase 2 (n = 14) because no dose-limiting toxicities occurred. In Phases 1 and 2, injection site reactions (n = 14, 77.8%) were the most common adverse events. All and DIPG patients showed the 9-month overall survival (OS) rates-the primary endpoint-of 44.4% (90% confidence interval (CI) [24.4-65.9]) and 27.3% [7.9-56.4], respectively. The vaccine was not effective statistically because the lower limit of the 90% CI for the primary efficacy endpoint in DIPG patients did not exceed its prespecified threshold-20%. Median OS was 5.4 months for DIPG. Among all patients, median OS was significantly longer (p = 0.024) for WT1-specific immune responders (9.9 months [6.0-33.4]) presenting increased CTL frequency/count and/or being positive for DTH than for nonresponders (4.9 months [2.2-16.5]). The vaccine was not effective statistically but was well tolerated and appeared to have induced WT1-specific immune responses, suggesting improved survival in WT1-specific immune responders among DIPG patients and warranting its further development. gov Identifier: NCT02750891.
2026-04-14 | An in-depth analysis of changes in the proteome and immunopeptidome after treatments in Diffuse Intrinsic Pontine Glioma (DIPG)
Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brain cancer with an average survival of only 9 months diagnosis. It is resistant to chemotherapy, and radiotherapy offers a limited increase in survival. DIPG is not easily recognised by the immune system as the signals it puts on the surface of the cells seem healthy. This thesis looked at whether treatment with new drugs in clinical trials would change these signals from something that looks healthy to something the immune system will recognise and kill. Once these signals are known, they can be used in a cancer vaccine.
2026-04-03 | Abstract 1270: Immunotoxin GB13 Targets GBM and H3.3K27M DIPG with the activation of Golgi-to-ER retrograde transport pathways.
Abstract GB13, an IL13Ra2-targeted immunotoxin, shows potent therapeutic potential against Glioblastoma (GBM) and H3.3K27M mutant Diffuse Midline Glioma (DIPG). The toxin, comprising Pseudomonas exotoxin A and IL-13 mutein, binds to IL13Ra2, which is frequently overexpressed on the surface of GBM and DIPG with histone 3.3 (H3.3) K27M mutation. GB13 is internalized through this binding and processed via Golgi-to-ER pathway. The active domain of the toxin is translocated to ADP-ribosylating eukaryotic elongation factor 2 (eEF-2) and halts protein synthesis, inducing apoptosis. In vitro drug dose-response assays demonstrated a 280-300 fold differential response in patient-derived GBM and DIPG models. Sensitivity correlated with IL13RA2 abundance and the H3.3K27M mutation. Gene Set Enrichment Analysis confirmed that sensitivity is linked to activated Golgi-to-ER retrograde transport pathways, the required trafficking route for GB13's cytotoxic release. Furthermore, these transport pathway scores negatively correlate with patient age in the TCGA-GBM dataset, suggesting demographic dependence. PBT29, the most sensitive H3.3K27M mutant DIPG line, showed the highest transport pathway enrichment. GB13's selective activity and its association with a Golgi-to-ER retrograde transport, as a predictive signature make it a highly promising candidate for these devastating diseases. The presence of these molecular signatures of vulnerability (mSov) could serve as an inclusion criterion for patient enrollment in clinical trials. Citation Format: Nanyun Tang, Yue Hao, Valerie DeLuca, Charles Caleb Shaffer, Randy Schrecengost, Michael E. Berens. Immunotoxin GB13 Targets GBM and H3.3K27M DIPG with the activation of Golgi-to-ER retrograde transport pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1270.
2026-03-13 | A RaPID macrocyclic peptide inhibitor of ROR1 strongly reduces proliferation of Diffuse Intrinsic Pontine Glioma cells
We report the de novo discovery of a cyclic peptide inhibitor of ROR1 from the RaPID (Random nonstandard Peptides Integrated Discovery) system. Multiple independent affinity selection campaigns converged on a highly conserved family of sequences exhibiting single digit nanomolar binding affinities to ROR1. One peptide from this family containing three non-proteinogenic residues, including a key cyclic β-amino acid, displayed pronounced activity in cellular assays. Strikingly, this peptide induced potent growth inhibition across multiple Diffuse Intrinsic Pontine Glioma (DIPG) cell lines, whereas other family members had no measurable cellular effects. Mechanistic analysis revealed that the active peptide uniquely competes with Wnt5a, the endogenous ligand of ROR1, for receptor binding. To our knowledge, this report provides the first evidence implicating ROR1 as a visible therapeutic target in DIPG and establishes macrocyclic peptides as a promising modality for its pharmacological inh
small molecules
2026-09-30 | Synergistic antitumor effect of HMGB2 targeting combined with MDM2 inhibitor in diffuse intrinsic pontine glioma therapy.
Diffuse intrinsic pontine glioma (DIPG) is a brain malignancy in children with a dismal prognosis. The high mobility group box 2 (HMGB2) is a member of the HMGB family of chromatin-associated proteins, and is identified as a potential oncogene in various cancers. However, the effects of HMGB2 in DIPG remains unclear. In this study, we observed aberrant expression of HMGB2 in multiple cancer types, with its expression level being negatively correlated with clinical outcomes across pan-cancers. High expression of HMGB2 was determined in DIPG cells, but not in primary brainstem neural progenitor cells (PPCs). Knockdown of HMGB2 significantly inhibited the DIPG cell proliferation and induced cell apoptosis. Intriguingly, bulk RNA sequencing revealed that inhibition of HMGB2 upregulated p53 protein expression and enhanced the activity of p53-p21 axis. Combining HMGB2 inhibitor with a p53-MDM2 inhibitor RG7388 resulted in a synergistic suppression of DIPG cell growth and promoted cell apoptosis by activating the tumor suppressor p53 and p21 expressions in vitro. The animal studies demonstrated that the combination treatment significantly inhibited tumor growth and prolonged the survival of mice bearing orthotopic DIPG tumors. These findings demonstrate that HMGB2 acts as an oncogene in DIPG tumorigenesis, and targeting HMGB2 combined with MDM2 inhibitor provides a novel preclinical basis for the development of DIPG therapeutic strategies.
2026-09-22 | Disruption of lamina-associated genome organization activates neuronal gene programs in H3.3K27M DIPG
Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor frequently driven by a histone H3 mutation that substitutes lysine 27 with methionine (H3K27M). While H3K27M is known to cause a global depletion of the repressive histone mark H3K27me3, how this epigenetic disruption contributes to oncogenic transcriptional reprogramming remains incompletely understood. Here, we show that H3.3K27M DIPG cells exhibit widespread disruption of lamina-associated domain (LAD) organization across primary tumors and patient-derived cell lines. H3.3K27M was enriched at genomic regions that lost lamina association, which acquired increased H3K27ac and showed activation of neuronal and oncogenic gene programs. Notably, LAD loss was more strongly associated with transcriptional activation than H3K27me3 depletion, linking altered LAD organization to the transcriptional consequences of H3.3K27M. Finally, expression of H3.3K27M in human embryonic stem cell-derived neural precursor cells (NPCs) was sufficient to induce LAD remodeling, predominantly through loss of lamina association, leading to activation of neuronal gene programs. Together, these findings identify disruption of lamina-associated genome architecture as a key mechanism by which the H3.3K27M oncohistone drives oncogenic transcriptional reprogramming in DIPG.
2026-09-17 | CNS distribution and preclinical activity of the PI3K/AKT inhibitors inavolisib and ipatasertib in pediatric-type diffuse high-grade gliomas.
Pediatric-type diffuse high-grade gliomas (pHGG) are aggressive, largely incurable malignancies often characterized by PI3K/AKT pathway activation. This study investigated whether the PI3K inhibitor inavolisib and the AKT inhibitor ipatasertib could achieve therapeutic concentrations in the central nervous system (CNS) and demonstrate efficacy against PIK3CA-mutated pHGG. A panel of 12 pHGG cell lines with diverse PI3K/AKT genetic aberrations was screened for sensitivity to inavolisib and ipatasertib. Pharmacokinetic (PK) modeling was performed in mice to determine brain-to-plasma exposure ratios following oral administration (50 mg/kg inavolisib and 100 mg/kg ipatasertib). Finally, the in vivo efficacy of both inhibitors was evaluated using intracranial PIK3CA-mutated pHGG xenograft models, with survival and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) levels as primary endpoints. All 12 cell lines exhibited PI3K/AKT alterations. The PIK3CA H1047R-mutated line (HSJD-DIPG-007) was the most sensitive in vitro (IC50 = 0.016 µM for inavolisib; 0.52 µM for ipatasertib). PK modeling revealed geometric mean brain-to-plasma ratios of 0.07 for inavolisib and 0.20 for ipatasertib, with model-predicted maximum brain concentrations of 0.69 µM and 0.93 µM, respectively. In vivo, inavolisib significantly extended survival (P = 0.0070) and increased CSF ctDNA release (P = 0.0317). In contrast, ipatasertib did not demonstrate significant in vivo activity. These findings highlight the therapeutic potential of inavolisib for treating PIK3CA-mutated pHGG. Despite the blood-brain barrier, inavolisib achieved sufficient CNS exposure to prolong survival in preclinical models, whereas ipatasertib efficacy did not translate from in vitro to in vivo settings.
2026-09-03 | Diffuse intrinsic pontine glioma in the era of H3 K27-altered diffuse midline glioma.
Diffuse intrinsic pontine glioma (DIPG), most commonly corresponding pathologically to diffuse midline glioma (DMG), H3 K27-altered, remains an overwhelmingly lethal pediatric brainstem malignancy, with median overall survival of approximately 11 months. We critically synthesized evidence identified through a structured search to December 31, 2025, supplemented by targeted updates of regulatory documents, clinical-trial records, and pivotal or practice-relevant publications through July 2026. We summarize epidemiology and the clinico-radiographic syndrome; examine the transition toward integrated molecular classification supported by stereotactic biopsy, with liquid biopsy emerging as a complementary tool; and distill core biology centered on PRC2 inhibition, loss of H3K27 trimethylation, developmental cell states, neuron-glioma interactions, and recurrent co-alterations involving TP53/PPM1D, ACVR1, PDGFRA, and PI3K/MAPK pathways. Radiotherapy remains the only modality with reproducible, albeit transient, clinical benefit; evidence supports hypofractionation in selected patients and reirradiation for carefully selected patients at recurrence. We appraise why cytotoxic chemotherapy and most targeted or epigenetic approaches have failed to deliver reproducible benefit, while highlighting early signals from CAR T-cell therapy, neoantigen vaccination, oncolytic virotherapy, and locoregional or ultrasound-enabled delivery. We also examine dordaviprone, the first systemic therapy to receive FDA accelerated approval for H3 K27M-mutant DMG with progressive disease following prior therapy, while emphasizing that the regulatory efficacy population excluded DIPG and therefore does not establish efficacy in classic pediatric pontine disease. Trial design must also explicitly separate anatomic phenotype from molecular taxonomy. Priorities include molecularly stratified enrollment, pharmacokinetically verified brainstem exposure, rational combinations, and endpoints integrating survival, neurologic function, and quality of life.
2026-09-01 | Integrated Transcriptomic and CRISPR Dependency Analysis Prioritizes a CDK1–AURKB Mitotic Vulnerability Axis in Diffuse Intrinsic Pontine Glioma
Abstract Diffuse intrinsic pontine glioma (DIPG), now classified within diffuse midline glioma, H3K27-altered, remains a lethal pediatric brainstem tumor with limited therapeutic options. Here, we integrated public DIPG transcriptomic datasets, protein–protein interaction modeling, functional enrichment, immune deconvolution, survival analysis, and DepMap CRISPR dependency data to nominate candidate mitotic vulnerabilities. Differential expression analysis comparing 27 DIPG tumors with 6 brainstem low-grade glioma comparator samples identified a proliferative transcriptional program enriched for chromosome segregation, nuclear division, and cell-cycle pathways. Network analysis prioritized a compact mitotic hub module containing CDK1, AURKB, TOP2A, CDC20, CDCA8, and related G2/M regulators. CIBERSORT analysis of an independent DIPG cohort inferred low cytotoxic T-cell signal, consistent with an immune-cold phenotype, although immune-cell fractions require orthogonal validation. Survival analysis showed that neither inferred immune scores nor a composite mitotic hub score significantly stratified overall survival. DepMap CRISPR gene-effect data nominated CDK1, AURKB, TOP2A, and BIRC5 as candidate dependencies across brain tumor models. These findings provide a computational framework for prioritizing mitotic vulnerabilities in DIPG and support experimental validation in disease-relevant models.
cell therapies
2026-09-01 | A CAR-T Tonic Signaling Code Predicts Anti-Tumor Efficacy in Diffuse Midline Glioma.
Diffuse middle glioma (DMG or DIPG) is a fatal pediatric brain tumor. Although chimeric antigen receptor (CAR) T-cell therapy shows promise, clinical outcomes remain inconsistent due to premature exhaustion, underscoring a critical need to improve CAR-T persistence. A major barrier to CAR-T efficacy is antigen-independent tonic signaling, yet the extent to which tonic signaling shapes CAR-T durability and clinical outcomes, particularly in DMG, remains incompletely defined. Using a clinically investigated B7-H3 MGA271-based CAR as a reference platform, we generated alternative B7-H3 CARs incorporating either a human codon-optimized 376.96 (B7H3.BC) or Hu8H9 scFv antigen binding domain to systematically assess scFv-dependent effects on tonic signaling and therapeutic efficacy. CAR-T cells were evaluated using integrated in vitro and in vivo functional assays, alongside multi-omics profiling and computational modeling. We further derived a tonic signaling-associated gene signature and evaluated its predictive performance across independent clinical datasets. B7H3.BC CAR-T cells exhibit markedly restrained tonic signaling compared with MGA271- and Hu8H9-based counterparts, accompanied by superior antitumor activity and enhanced persistence across patient-derived DMG cells. Integrated multi-omics and single-cell profiling further identified a tonic signaling-associated gene signature that outperforms conventional T-cell exhaustion signatures in predicting therapeutic efficacy across multiple clinical trials, including DMG and other tumors. Our findings establish that scFv-dependent modulation of tonic signaling critically governs CAR-T persistence and antitumor efficacy in DMG. By linking CAR design to transcriptional and epigenetic programs, our study provides a principle-based and predictive framework to inform rational CAR engineering and improve therapeutic outcomes.
2026-08-08 | CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13Rα2, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.
2026-08-07 | Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
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. 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. 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. 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.
2026-07-01 | Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial.
Central nervous system (CNS) tumors are the deadliest cancers in children, highlighting the need for new therapies. The tumor-associated antigens (TAAs) WT1, PRAME and survivin are widely expressed by these tumors, and a manufacturing technique has been developed to target these intracellular TAAs using autologous, nongenetically engineered T cells. Here we therefore conducted ReMIND, an open-label, phase 1 adaptive dose-finding study to determine the safety/feasibility of autologous, systemically administered trivalent T cells targeting WT1, PRAME and survivin in children with CNS tumors. Eligible patients had newly diagnosed diffuse intrinsic pontine glioma without lymphodepletion (arm A, n = 16 enrolled, n = 11 infused) and relapsed/recurrent nonbrainstem CNS malignancies without (arm B, n = 28 enrolled, n = 18 infused) or with (arm C, n = 7 enrolled, n = 4 infused) lymphodepletion. Primary end points were safety, feasibility and maximum tolerated dose determination; secondary end points included preliminary efficacy and immunobiological correlates, including in vivo TAA-T persistence and systemic immune activation. Dose level 3 (8 × 107 cells per m2 per dose) was determined as the maximum tolerated dose. Treatment was well tolerated with fatigue and headache being the most common adverse events, although two possibly related serious adverse events of tumor swelling occurred. One grade 5 event in a patient with diffuse intrinsic pontine glioma with hydrocephalus, tumor edema and respiratory failure was categorized as a dose-limiting toxicity. Median overall survival for arm A was 13.7 months from diagnosis (range, 6.2-32.0) and median progression-free survival for arms B/C was 5.0 months from infusion (range, 0.5-51.6). Three patients in arms B/C are alive without disease at 31.8, 41.2 and 51.6 months without further treatment, including one complete response. This trial met safety/feasibility primary end points with some preliminary signals of efficacy. ClinicalTrials.gov registration: NCT03652545 .
antibodies
2026-09-22 | Integrated multi-omics identifies lineage-dependent myeloid cells recruitment and the APP-CD74 axis as an immunoregulatory target in pediatric high-grade glioma.
Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with limited treatment options. Emerging evidence indicates infiltration of tumor-associated macrophages (TAMs) within tumor sites, accompanied by an immunosuppressive tumor microenvironment (TME). However, the mechanisms underlying macrophage recruitment and communication between TAMs and other cellular compartments within brain tumors remain poorly understood. Bulk RNA sequencing of 26 DIPG autopsy specimens with matched normal brain tissue, single-cell RNA sequencing data from eight DIPG patients integrated with public pediatric high-grade glioma (pHGG) datasets, and in vitro transwell and flow cytometry assays collectively indicated that DIPG tumors actively recruit monocytes through chemokine-mediated mechanisms. The chemokine expression of tumor cells is driven by a mesenchymal-like (MES-like) lineage state rather than histone mutations, as evidenced by significant correlation between MES-like lineage scores and chemokine expression scores across 46 pHGG cell lines. CellChat analysis predicted APP-CD74 signaling as a prominent tumor cell-TAM interaction pathway, supported by immunofluorescence validation. Notably, APP expression was significantly reduced in DIPG tumor tissues compared with normal brain tissue at both the RNA and protein levels. Recombinant APP stimulation of THP-1-derived macrophages induced a robust proinflammatory response, including upregulation of M1-like markers, enrichment of interferon-related pathways, and elevated secretion of inflammatory cytokines. Collectively, these findings suggest that reduced APP expression in tumor may contribute to a non-inflammatory TAM phenotype and an immunosuppressive microenvironment. Furthermore, protein modeling and docking analyses identified the APP-CD74 binding interface, providing a structural basis for therapeutic targeting.
2026-06-30 | Pediatric Brain Tumor Consortium phase 1 study of CD40 agonist sotigalimab in pediatric and young adult patients with recurrent CNS tumors and newly-diagnosed DIPG.
The PBTC-051 study is the first pediatric evaluation of a CD40 agonist and assessed the safety, pharmacokinetics, and preliminary efficacy of sotigalimab in children and young adults with recurrent or progressive malignant central nervous system (CNS) tumors (stratum 1) and post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) (stratum 2). This prospective phase 1 study conducted by the Pediatric Brain Tumor Consortium evaluated sotigalimab using a 3+3 design for dose escalation. Immune pharmacodynamics were assessed with RNA transcript analysis, T cell receptor sequencing, and cytokine profiling. 31 eligible patients were enrolled (stratum 1: 20, stratum 2: 11). The stratum 1 recommended phase 2 dose was 0.6 mg/kg every 3 weeks; the stratum 2 maximum tolerated dose was 0.3 mg/kg every 3 weeks. Five patients had dose-limiting toxicities. No patients had an objective response. For stratum 1, 6-month and 12-month progression-free survivals (PFS) were 13.3% (standard error [SE], 8.1%) and 6.7% (SE, 6.2%), respectively; for stratum 2, 6-month PFS and overall survival were 31.2% (SE, 14.8%) and 44.4% (SE, 16.6%), respectively. At all dose levels, the maximum serum concentration was reached at the end of infusion; no drug accumulation was detected. More than 40% of patients developed anti-drug antibodies. Signaling pathways associated with activated antigen presenting cells and T cells were enriched in patients with higher PFS, while increased loss of heterozygosity was noted in patients with lower PFS. Sotigalimab was well-tolerated in pediatric patients with recurrent or progressive CNS tumors and post-radiation pre-progression DIPG.
2026-06-29 | Tumor-Targeted pan-RAS Inhibition as a Novel Biologic Therapy for Diffuse Midline Glioma.
Pediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer-related deaths. Those arising in the midline harboring a lysine to methionine substitution at position 27 in histone 3 (H3K27M), termed diffuse midline glioma (or DIPG when occurring in the pons), are particularly deadly and in need of additional therapeutic options. Our group and others have found upregulation of the RAS/MAPK pathway across HGGs, including DIPG; however, RAS is notoriously difficult to target therapeutically, with no approved drugs that can target non-mutant RAS proteins. We leveraged a pan-RAS-cleaving biologic (RRSP-DTB) to define RAS dependency in DIPG and employed proteomic profiling of patient-derived tumors to identify enriched cell-surface receptors for tumor-selective targeting. RRSP was re-engineered to engage the lead candidate receptor, tumor endothelial marker 8 (TEM8/ANTXR1), generating a targeted RAS-degrading biologic evaluated in vitro and in orthotopic DIPG xenograft models. Pan-RAS cleavage revealed DIPG to be critically dependent on RAS/MAPK signaling compared to other RAS/MAPK HGGs. Targeting RRSP to TEM8 enabled efficient intracellular delivery, resulting in complete RAS ablation and apoptotic cell death in patient-derived DIPG cells at low picomolar concentrations. In vivo, intracerebroventricular delivery reduced leptomeningeal disease burden (p = 0.04), while convection-enhanced delivery extended survival in orthotopic DIPG models (median survival 68 vs. 57 days; p = 0.016). We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.
2026-06-23 | ID #315 The Impact of Bevacizumab on Quality of Life in Diffuse Intrinsic Pontine Glioma (DIPG) Patients: A Systematic Review
Abstract Background Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive pediatric brain tumor, typically resistant to treatment. Despite advancements in therapeutic approaches like radiation, prognosis remains poor. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has shown potential in alleviating tumor-related symptoms but its effect on the quality of life (QoL) of DIPG patients is still uncertain. Methods A systematic review was conducted using databases such as PubMed, Google Scholar, Science Direct, and EBSCOhost, examining studies published in the last ten years. The inclusion criteria focused on studies assessing the impact of Bevacizumab on QoL for children with DIPG. Studies using quality of life assessment tools such as the Pediatric Quality of Life Inventory (PedsQL) were included. Results Five studies were included in the review, and the findings suggested temporary improvements in cognitive and physical functioning during treatment with Bevacizumab. Common side effects included lymphopenia and thrombocytopenia. However, long-term survival outcomes remained limited, with median survival ranging from 13.8 to 14 months. Conclusion Bevacizumab may provide short-term symptomatic relief in DIPG patients, particularly in cognitive and physical domains, but its limited impact on long-term survival and overall QoL highlights the need for further research into targeted therapies and personalized treatments. Future studies should focus on improving survival outcomes and refining combination therapies to enhance patient well-being. 1. 1. Hummel TR, Salloum R, Rachid Drissi, Kumar S, Sobo M, Goldman S, et al. A pilot study of bevacizumab- based therapy in patients with newly diagnosed high-grade gliomas and diffuse intrinsic pontine gliomas. Journal of neuro-oncology. 2015 Dec 1;127(1):53–61. 2. Jansen MH, Veldhuijzen van Zanten SEM, van Vuurden DG, Huisman MC, Vugts DJ, Hoekstra OS, et al. Molecular Drug Imaging:89Zr- Bevacizumab PET in Children with Diffuse Intrinsic Pontine Glioma. Journal of Nuclear Medicine. 2016 Oct 20;58(5):711–6. 3. Crotty EE, Leary SES, Geyer JR, Olson JM, Millard NE, Sato AA, et al. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. Journal of Neuro-Oncology. 2020 Jun 16;148(3):607–17. 4. El-Khouly FE, Sophie, Marc, Bakker DP, Aliaga ES, Hendrikse NH, et al. A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma. Journal of Neuro- Oncology. 2021 May 7;153(2):263–71. 5. Honda M, Fukuoka K, Tanami Y, Kurihara J, Koh K. Bevacizumab for the early clinical progression of diffuse intrinsic pontine glioma. Pediatrics International [Internet]. 2023 Jan [cited 2026 Jan 11];65(1).
2026-04-03 | Abstract 644: Evaluating GD2-targeting antibody-drug conjugates for DIPG using human organoid-based preclinical platforms.
Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with a median survival of less than 12 months. Although the recent FDA accelerated approval of ONC201 offers a long-awaited sense of progress for the DIPG/DMG community, the central therapeutic problem remains far from solved. The frequent presence of H3K27M mutations in DIPG is associated with elevated expression of GD2, a clinically actionable surface antigen. GD2-directed CAR-T therapies have shown encouraging early activity in DIPG. However, challenges such as antigen heterogeneity, inherent manufacturing lead time, and risks of neurotoxicity remain. Antibody-drug conjugates (ADCs) offer a more controllable, off-the-shelf therapeutic approach that could overcome these limitations, yet their potential in DIPG remains unexplored. To evaluate the efficacy, resistance, and safety of GD2-targeting ADCs, we employed two complementary human-derived organoid platforms. First, DIPG models were generated using NanoGlio, a high-throughput nanoliter-volume droplet 3D organoid system. Second, we established a co-culture model with DIPG NanoGlio and iPSC-derived brain organoids to assess neurotoxicity. We successfully generated NanoGlio derived from 9 DIPG models reflecting the key genetic alterations typically identified in DIPG, including mutations in H3.3 (H3F3A) or H3.1 (HIST1H3B). We assessed the expression of GD2 by flow cytometry and 3D-Fluorescence Antibody Cell Tracking (3D-FACT) and observed widely variable GD2 expression across DIPG models. We tested M3554, a first-in-class clinical-stage anti-GD2 ADC conjugated to exatecan, a topoisomerase I inhibitor, in these models. M3554 exhibited potent cytotoxicity across DIPG NanoGlios. Resistance profiling using its unconjugated payload, Exatecan, revealed that reduced ADC response was primarily driven by intrinsic payload resistance rather than low GD2 expression. DIPG models with very low GD2 expression, including SF7761 and SU-DIPG-IV, also responded strongly to M3554, consistent with a bystander killing effect. iPSC-derived brain organoids (GD2-negative) showed minimal toxicity with M3554, whereas equivalent doses of Exatecan induced extensive cell death. Future work will systematically evaluate GD2 ADC bystander effect via co-encapsulation of GD2+ and GD2- DIPG cells, and assess the efficacy and neurotoxicity of M3554 using our DIPG-brain co-culture model. Successful completion of this study will provide critical preclinical evidence supporting the assessment and use of GD2-targeting ADCs in DIPG treatment. Citation Format: Zhikun Wang, Emily Miller, Wei Huang, Satoru Kawakita, Lauren Vanderpool, Francisco Bustamante, Uijin Kim, Zhaohui Wang. Evaluating GD2-targeting antibody-drug conjugates for DIPG using human organoid-based preclinical platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 644.
gene therapies
2026-09-26 | Virotherapy for Spinal and Spinal Cord Tumors: Current Evidence and Future Perspectives.
Tumors of the spine and spinal cord, including primary and metastatic vertebral tumors, intramedullary gliomas, and refractory intradural lesions, are challenging to treat because curative local therapy is limited by the eloquent, nonregenerating neural tissue surrounding them. Oncolytic virotherapy may offer a rational alternative by combining tumor-selective oncolysis with the induction of systemic antitumor immunity, while sparing normal neural cells. This review summarizes the current field of oncolytic viruses, including adenovirus, herpes simplex virus, reovirus, and others, in the context of spinal and spinal cord tumors. Clinical data in the spine remain scarce; however, the rationale is based on histological evidence from sarcomas and other tumors, extensive glioma experience, including diffuse intrinsic pontine glioma, and preclinical activity in nerve sheath and meningioma models. We discuss the telomerase-specific oncolytic adenovirus OBP-301 and its derivatives, whose hTERT-driven replication provides histology-agnostic tumor selectivity, while sparing the telomerase-silent spinal cord. This telomerase dependence, however, limits activity against tumors that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, such as many osteosarcomas and some spinal cord astrocytomas. We also discuss delivery and safety within the confined spinal canal, combination strategies, and future directions, such as extracellular vesicle-mediated delivery and biomarker-guided patient selection. Although clinical translation to the spine will require dedicated preclinical and early-phase studies, virotherapy represents a promising, mechanistically grounded modality for these therapeutically challenging tumors.
2026-06-17 | Modeling diffuse midline glioma through triple-electrode in utero electroporation of the developing mouse pons.
The leading cause of brain cancer-related death in children is diffuse midline glioma (DMG). A particularly aggressive DMG subtype is pontine DMG (formerly diffuse intrinsic pontine glioma, DIPG), which is caused by the histone mutation H3.3K27M. Because of its diffuse growth and location in a critical brainstem structure, therapeutic options are limited, and pontine DMG is considered universally fatal. The lack of appropriate animal models has hindered our understanding of the developmental origins and progression of pontine DMG, which in turn has limited the development of effective therapeutics. To address this barrier, several labs have developed mouse in utero electroporation approaches to express canonical DMG mutant oncogenes in the developing pons. In this manuscript and accompanying protocol, we describe a modified in utero electroporation strategy to generate DMG tumors in the developing mouse pons. Our protocol incorporates a single plasmid construct that expresses canonical DMG oncogenes, eliminating the need to co-electroporate multiple plasmids. We also employ a triple-electrode configuration to precisely target neural progenitors lining the fourth ventricle, which give rise to cells in the pons. As the embryos continue to develop in utero and postnatally, they form large, diffuse brainstem tumors with molecular characteristics of pediatric pontine DMG, allowing us to model the formation and progression of this deadly pediatric brain cancer.
2026-02-18 | A Decade of Oncolytic Virotherapy in Pediatric Cancers: A Systematic Review of Safety, Immune Awakening, and Emerging Efficacy.
Oncolytic virotherapy employs genetically modified viruses to selectively lyse tumor cells while activating antitumor immune responses. In pediatric oncology, where outcomes for high-grade gliomas and refractory solid tumors remain poor, oncolytic viruses represent a promising therapeutic strategy. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, including searches of PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov for studies published between 2015 and 2025 that evaluated oncolytic virotherapy in patients aged 18 years or younger. Data on safety, efficacy, and immune-related outcomes were extracted, study quality was assessed using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool, and the certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Ten early-phase clinical trials involving 115 pediatric patients met the inclusion criteria. Investigated viral platforms included herpes simplex virus type 1 (G207, HSV1716), adenovirus (DNX-2401, ICOVIR-5, Ad-TD-nsIL12), T-VEC (HSV-1), poliovirus (PVSRIPO), Seneca Valley virus, and reovirus. Across studies, no treatment-related deaths or persistent grade 3 or higher toxicities were reported, and adverse events were generally mild and transient. Radiologic or clinical disease control rates ranged from 20% to 90%, with median overall survival between 11 and 18 months in selected central nervous system tumor cohorts. Translational analyses demonstrated increased CD8⁺ T-cell infiltration, upregulation of interferon-γ and interleukin-6 signaling pathways, and evidence of transient viral replication, supporting immune-mediated antitumor mechanisms. Overall risk of bias was moderate, while the certainty of evidence was rated as low for safety outcomes and very low for efficacy. These findings indicate that oncolytic virotherapy is safe, feasible, and biologically active in children with malignant brain and solid tumors, and that preliminary survival signals and consistent immune activation support further investigation through larger, multicenter randomized trials and combination strategies with radiotherapy or immune checkpoint inhibitors.
2026-01-28 | Tropism Profiling of Lentiviral Vector Pseudotypes in Diverse Brain Tumor Models.
Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants-VSV-GP, FuG-B2, and LCMV-GP-across diverse brain tumor cell lines including glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, and metastatic brain cancers. Results: VSV-GP and FuG-B2 pseudotypes significantly outperformed LCMV-GP across most tumor types. Both VSV-GP and FuG-B2 demonstrated high transduction efficiency in GBM and DIPG cells, though some cell lines displayed selective preferences for one pseudotype over the other. Medulloblastoma cells were challenging to transduce, with only VSV-GP achieving substantial efficacy. Metastatic brain cancers showed distinct tropism patterns: melanoma metastases were preferentially transduced by the FuG-B2 pseudotype, while lung metastases showed preference for the VSV-GP pseudotype. Conclusions: These findings suggest envelope protein selection should be tailored to specific brain tumor types. VSV-GP appears most suitable for medulloblastoma and lung metastases, FuG-B2 for melanoma metastases, and both for GBM and DIPG gene therapy applications. The study provides crucial guidance for translating lentiviral gene therapy to clinical applications, supporting personalized treatment strategies based on tumor-specific vector tropism profiles.
2025-12-09 | [Current Status and Future Perspectives of Clinical Trials for Diffuse Intrinsic Pontine Gliomas(DIPG)].
Diffuse intrinsic pontine glioma (DIPG) remains one of the most devastating pediatric central nervous system tumors, with a median survival of approximately 11 months despite decades of research. The identification of histone H3 K27M mutations marked a pivotal moment, leading to major advancements in understanding the molecular and epigenetic characteristics of these tumors. This discovery enabled molecular classification and provided a basis for the development of novel therapeutic strategies. In recent years, clinical trials have investigated molecular targeted agents and epigenetic modulators. Immunotherapeutic approaches, such as CAR-T cell therapy, have shown promising early results, whereas innovative drug delivery techniques, including convection-enhanced delivery and focused ultrasound, aim to overcome the challenges of the blood-brain barrier. Two major international registries, the International DIPG/DMG Registry (IDIPGR) and the European Society for Paediatric Oncology (SIOPE) DIPG/DMG Registry, play crucial roles in collecting comprehensive clinical data across multiple countries. The DIPG-2023 registry study was launched in Japan to collect prospective clinical, radiological, and molecular data systematically and to provide a high-quality external control cohort for future intervention trials. These collaborative efforts highlight a new era of DIPG/DMG research, offering cautious optimism for therapeutic progress in this historically refractory disease.
other
2026-06-09 | A RaPID Macrocyclic Peptide Inhibitor of ROR1/2 Strongly Reduces Proliferation of Diffuse Intrinsic Pontine Glioma Cells.
We report the de novo discovery of a cyclic peptide inhibitor of ROR1/2 from the RaPID (random nonstandard peptides integrated discovery) system. Multiple independent affinity selection campaigns converged on a highly conserved family of sequences exhibiting single-digit nanomolar binding affinities to ROR1. One peptide from this family containing three nonproteinogenic residues, including a key cyclic β-amino acid, displayed pronounced activity in cellular assays. Strikingly, this peptide induced potent growth inhibition across multiple Diffuse Intrinsic Pontine Glioma (DIPG) cell lines, whereas other family members had no measurable cellular effects. Mechanistic analysis revealed that the active peptide uniquely competes with Wnt5a, the endogenous ligand of ROR1, for receptor binding. To our knowledge, this report provides the first evidence implicating ROR1/2 as a viable therapeutic target in DIPG and establishes macrocyclic peptides as a promising modality for its pharmacological inhibition.
2026-05-24 | Phase 1/2 study of a WT1 peptide-dosing emulsion in pediatric patients with recurrent/refractory diffuse intrinsic pontine glioma, glioblastoma, or anaplastic astrocytoma.
The prognosis of pediatric patients with diffuse intrinsic pontine glioma (DIPG), glioblastoma, or anaplastic astrocytomas (AAs) is dismal. This first-in-child phase 1/2 study examined the safety and efficacy of a Wilms' tumor gene 1 (WT1) peptide vaccine, along with the associations of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) frequency/count with clinical outcomes. Patients (<20 years) were intradermally injected with the vaccine. Among all patients (N = 18; median age: 8.9 years), 11, 5, and 2 had DIPG, glioblastoma, and AAs, respectively. In Phase 1 (n = 4), 3.5 mg was determined for use in Phase 2 (n = 14) because no dose-limiting toxicities occurred. In Phases 1 and 2, injection site reactions (n = 14, 77.8%) were the most common adverse events. All and DIPG patients showed the 9-month overall survival (OS) rates-the primary endpoint-of 44.4% (90% confidence interval (CI) [24.4-65.9]) and 27.3% [7.9-56.4], respectively. The vaccine was not effective statistically because the lower limit of the 90% CI for the primary efficacy endpoint in DIPG patients did not exceed its prespecified threshold-20%. Median OS was 5.4 months for DIPG. Among all patients, median OS was significantly longer (p = 0.024) for WT1-specific immune responders (9.9 months [6.0-33.4]) presenting increased CTL frequency/count and/or being positive for DTH than for nonresponders (4.9 months [2.2-16.5]). The vaccine was not effective statistically but was well tolerated and appeared to have induced WT1-specific immune responses, suggesting improved survival in WT1-specific immune responders among DIPG patients and warranting its further development. gov Identifier: NCT02750891.
2026-04-14 | An in-depth analysis of changes in the proteome and immunopeptidome after treatments in Diffuse Intrinsic Pontine Glioma (DIPG)
Diffuse Intrinsic Pontine Glioma (DIPG) is a childhood brain cancer with an average survival of only 9 months diagnosis. It is resistant to chemotherapy, and radiotherapy offers a limited increase in survival. DIPG is not easily recognised by the immune system as the signals it puts on the surface of the cells seem healthy. This thesis looked at whether treatment with new drugs in clinical trials would change these signals from something that looks healthy to something the immune system will recognise and kill. Once these signals are known, they can be used in a cancer vaccine.
2026-04-03 | Abstract 1270: Immunotoxin GB13 Targets GBM and H3.3K27M DIPG with the activation of Golgi-to-ER retrograde transport pathways.
Abstract GB13, an IL13Ra2-targeted immunotoxin, shows potent therapeutic potential against Glioblastoma (GBM) and H3.3K27M mutant Diffuse Midline Glioma (DIPG). The toxin, comprising Pseudomonas exotoxin A and IL-13 mutein, binds to IL13Ra2, which is frequently overexpressed on the surface of GBM and DIPG with histone 3.3 (H3.3) K27M mutation. GB13 is internalized through this binding and processed via Golgi-to-ER pathway. The active domain of the toxin is translocated to ADP-ribosylating eukaryotic elongation factor 2 (eEF-2) and halts protein synthesis, inducing apoptosis. In vitro drug dose-response assays demonstrated a 280-300 fold differential response in patient-derived GBM and DIPG models. Sensitivity correlated with IL13RA2 abundance and the H3.3K27M mutation. Gene Set Enrichment Analysis confirmed that sensitivity is linked to activated Golgi-to-ER retrograde transport pathways, the required trafficking route for GB13's cytotoxic release. Furthermore, these transport pathway scores negatively correlate with patient age in the TCGA-GBM dataset, suggesting demographic dependence. PBT29, the most sensitive H3.3K27M mutant DIPG line, showed the highest transport pathway enrichment. GB13's selective activity and its association with a Golgi-to-ER retrograde transport, as a predictive signature make it a highly promising candidate for these devastating diseases. The presence of these molecular signatures of vulnerability (mSov) could serve as an inclusion criterion for patient enrollment in clinical trials. Citation Format: Nanyun Tang, Yue Hao, Valerie DeLuca, Charles Caleb Shaffer, Randy Schrecengost, Michael E. Berens. Immunotoxin GB13 Targets GBM and H3.3K27M DIPG with the activation of Golgi-to-ER retrograde transport pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1270.
2026-03-13 | A RaPID macrocyclic peptide inhibitor of ROR1 strongly reduces proliferation of Diffuse Intrinsic Pontine Glioma cells
We report the de novo discovery of a cyclic peptide inhibitor of ROR1 from the RaPID (Random nonstandard Peptides Integrated Discovery) system. Multiple independent affinity selection campaigns converged on a highly conserved family of sequences exhibiting single digit nanomolar binding affinities to ROR1. One peptide from this family containing three non-proteinogenic residues, including a key cyclic β-amino acid, displayed pronounced activity in cellular assays. Strikingly, this peptide induced potent growth inhibition across multiple Diffuse Intrinsic Pontine Glioma (DIPG) cell lines, whereas other family members had no measurable cellular effects. Mechanistic analysis revealed that the active peptide uniquely competes with Wnt5a, the endogenous ligand of ROR1, for receptor binding. To our knowledge, this report provides the first evidence implicating ROR1 as a visible therapeutic target in DIPG and establishes macrocyclic peptides as a promising modality for its pharmacological inh
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Drug Discovery Landscape
5 orphan drug designations for Diffuse intrinsic pontine glioma.
5 orphan drug designations for Diffuse intrinsic pontine glioma.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Humanised IgG1 kappa monoclonal antibody against erythropoietin isoform EV-3 | antibodies | EMA | — | Andremacon S.r.l. |
Iniparib | small molecules | EMA | Raremoon Consulting Esp S.L. | |
1,2:5,6-dianhydrogalactitol | small molecules | FDA | Kintara Therapeutics, Inc. | |
dimethylaminomicheliolide Fumarate | small molecules | FDA | Accendatech AU Pty Ltd. | |
A10 & AS2-1 Antineoplaston | peptides | FDA | Burzynski Research Institute, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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