Neurooncol Adv. 2025 May 13;7(1):vdaf093. doi: 10.1093/noajnl/vdaf093. eCollection 2025 Jan-Dec.

ABSTRACT

BACKGROUND: Median survival in patients with diffuse intrinsic pontine glioma (DIPG) varies between 11 months for children and 20 months for adults. There is no standard of care treatment other than radiation therapy. This study aimed to determine the safety, tolerability, and distribution of nanoliposomal irinotecan (nal-IRI) delivered via CED in patients with DIPG.

METHODS: Newly diagnosed DIPG patients > 2 years were eligible for enrollment. Dose level (DL) 1 and 2 were completed (DL1 = 2 mL of nal-IRI [20 mg/mL] DL2 = 3 mL of nal-IRI [20 mg/mL]). Nal-IRI was co-infused with gadoteridol via CED to achieve maximal tumor coverage. The distribution of infusate mixture was monitored with real-time magnetic resonance imaging (MRI). The study employed an accelerated dose escalation approach and transitioned to a conventional 3 + 3 design based on predefined rules. The study was terminated prematurely due to the discontinuation of drug supply by industry partner.

RESULTS: Six patients (median age 10 years, range 5-40) underwent a total of 13 treatments (median 2, range 1-5/patient). Four grade 3 adverse events, (muscle weakness n = 2, dysarthria n = 1, and gait disturbance n = 1) were observed, including one dose-limiting toxicity (muscle weakness). Mean tumor volume prior to the first CED treatment was 28.9 ± 8.8 cm³ with a mean tumor coverage per treatment of 35.3% ± 17.6. Twelve-month overall survival (OS) was 67% (95% CI 38-100).

CONCLUSIONS: Repeated CED of nal-IRI in patients with DIPG demonstrated an acceptable risk profile with reasonable tumor coverage. Additional investigations utilizing this strategy should be evaluated in a larger patient cohort to determine efficacy.

PMID:40575415 | PMC:PMC12202035 | DOI:10.1093/noajnl/vdaf093

Cell Rep Med. 2025 Jun 23:102204. doi: 10.1016/j.xcrm.2025.102204. Online ahead of print.

ABSTRACT

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.

PMID:40578365 | DOI:10.1016/j.xcrm.2025.102204

Int J Radiat Oncol Biol Phys. 2025 Jun 19:S0360-3016(25)00532-2. doi: 10.1016/j.ijrobp.2025.05.063. Online ahead of print.

ABSTRACT

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric malignancy of the brainstem with a lack of effective therapeutic options. This study assesses the efficacy and safety of adding nimotuzumab to temozolomide (TMZ) chemoradiation therapy for newly diagnosed pediatric DIPG.

METHODS AND MATERIALS: We conducted an open-label, single-arm, prospective, multicenter study involving children aged 3-15 years with histologically or radiographically confirmed DIPG from April 3, 2021 to April 13, 2023. Nimotuzumab (150 mg/m²/wk) was administered concurrently with local radiation therapy (54 Gy/30 f) and TMZ (75 mg/m²/d) for 6 weeks, followed by adjuvant TMZ (150-200 mg/m² for 5 consecutive days of a 28-day cycle for 6 cycles) and nimotuzumab (150 mg/m² biweekly until to disease progression). The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Adverse events were summarized using descriptive statistics.

RESULTS: Of 48 enrolled patients, with a median age of 7 years (4-14), 28 (58.3%) were histologically confirmed, and 25 (89.3%) had H3K27M mutations. With a median follow-up of 26.5 months (95% CI, 14.6-not applicable), the ORR was 37.5%; the median OS and PFS were 10.5 (8.3-11.2) and 7.8 (5.1-8.4) months; and 1-year OS and PFS rates were 33.3% and 26.9%, respectively. Multivariate analysis showed that a partial response and no steroid use were associated with favorable OS. Distant metastasis was observed in 7 patients (14.6%). The most common grade ≥ 3 treatment-related adverse events were leukopenia (27.1%), lymphopenia (27.1%), and neutropenia (25.0%).

CONCLUSIONS: Adding nimotuzumab to chemoradiation therapy is feasible, with ORR and survival rates favorably comparable with previous data in pediatric DIPG, despite not meeting the prespecified statistical significance for improved ORR compared with historical data. The overall safety profile was manageable, with no new safety concerns.

PMID:40536469 | DOI:10.1016/j.ijrobp.2025.05.063

NPJ Precis Oncol. 2025 Jun 14;9(1):184. doi: 10.1038/s41698-025-00956-z.

ABSTRACT

High-grade gliomas (HGGs), including glioblastoma (GBM) and pediatric diffuse midline gliomas (DMGs), remain highly fatal despite therapeutic advances. The tumor microenvironment (TME), particularly the extracellular matrix (ECM), plays a crucial role in tumor progression, immune exclusion, and drug resistance. We performed a comprehensive proteomic, transcriptomic, and pathological characterization of the ECM in primary adult and pediatric HGGs. Using cell surface proteomics, TCGA transcriptomics, and immunohistochemistry, we identified key ECM components influencing immune infiltration. We integrated these findings into ImmunoTar, a computational model prioritizing immunotherapeutic targets. Our study presents the first in-depth cell surface proteomic landscape of HGG ECM, identifying CSPG4/5, PTPRZ1, SDC1, TGFBR3, PLG, and GPC2 as key targets. We validate ECM-targeted CAR T cell therapy, including Glypican-2 (GPC2), which shows strong efficacy against pediatric DIPG. These findings highlight ECM-focused immunotherapy as a promising strategy to overcome HGGs' immunosuppressive TME, particularly in pediatric patients.

PMID:40517137 | PMC:PMC12167366 | DOI:10.1038/s41698-025-00956-z

J Immunother Cancer. 2025 Jun 12;13(6):e012009. doi: 10.1136/jitc-2025-012009.

ABSTRACT

Diffuse intrinsic pontine glioma (DIPG) is a rare and highly aggressive pediatric brain tumor with a median survival of less than 12 months. The tumor arises in the pons, making surgical resection unfeasible and limiting treatment options to palliative radiation, which offers minimal survival benefit. One of the major challenges in treating DIPG is the poorly understood tumor immune microenvironment, which has hindered the development of effective immunotherapies. DIPG tumors are considered to be immunologically cold with limited immune cell infiltration. Recent studies have begun to reveal the complex and heterogeneous immune landscape of DIPG, highlighting distinct immunological subgroups. This review aims to provide a comprehensive overview of the immune landscape of DIPG based on the latest insights, identify research gaps, and suggest potential areas for future investigation to improve treatment outcomes for patients with DIPG.

PMID:40514066 | PMC:PMC12164617 | DOI:10.1136/jitc-2025-012009

Cells. 2025 May 23;14(11):772. doi: 10.3390/cells14110772.

ABSTRACT

Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic potential of genetic and pharmacologic inhibition of the cargo receptor TMED9 in glial tumor models. Our findings demonstrate that TMED9 expression is upregulated in glioma and that this upregulation is associated with poor patient survival. Using patient-derived glioma tumor cells, we demonstrate that TMED9 is highly expressed in the cancer stem cell population and that this upregulation promotes the cells' self-renewal and migration. This is the first time, to the best of our knowledge, that TMED9 has been shown to play a major role in the function and tumorigenesis of brain tumor cancer stem cells. BRD4780, a small molecule that targets TMED9, effectively reduced TMED9 abundance, resulting in decreased viability, migration and stemness of patient-derived glioma stem cells. Moreover, BRD4780 mitigated the proliferation and migration of differentiated glioma tumor cells. When applied together with temozolomide, an established glioblastoma treatment, BRD4780 elicited an enhanced anti-tumor response. Lastly, to demonstrate the broad applicability of our findings, we targeted TMED9 in pediatric glioma cells and showed efficient inhibition of various oncogenic functions. Collectively, our study identifies TMED9 inhibition as a promising therapeutic approach that impairs the tumorigenesis and aggressiveness of brain tumors, with high efficacy against the tumor stem cell population. The effectiveness of TMED9 targeting in different tumor cell populations, the potential of combining this strategy with established therapies and the broad applicability of this approach to multiple cancer types highlight the significance of these findings.

PMID:40497947 | PMC:PMC12153874 | DOI:10.3390/cells14110772