Pediatric Brain Tumor Foundation

Abstract The care of patients with meningioma is often multidisciplinary due to potential tumor and treatment morbidity, evolving biomarkers, high rates of recurrence in select subgroups, and emerging systemic therapies. UCSF previously convened two tumor boards for adult brain tumor patients, one general (median 14 patients/week, range 4-25) and one specific for stereotactic radiosurgery (median 13 patients/week, range 5-28). Due to patient volume, a separate meningioma multidisciplinary tumor board (MMTB) and meningioma multidisciplinary clinic (MMDC) were initiated in 9/2024. The UCSF MMTB is a weekly meeting of healthcare providers from neurosurgery, radiation oncology, neuro-oncology, neuropathology, neuroradiology, and neuro-ophthalmology (median 20 providers/week, range 11-24). Next-generation sequencing is performed on all resected meningiomas, and results of molecular testing, imaging studies, and therapeutic interventions are reported at the UCSF MMTB. Postoperative cases are seen in-house by a nurse practitioner to establish continuity of care (median 13 consults/month). From 9/2024 to 5/2025, the UCSF MMTB discussed 421 cases (median 13 patients/week, range 5-23, 34.5% recurrent). An additional 219 cases screened out of discussion based on reassuring histological and molecular features (median 21 total patients triaged/week, range 10-36). Median age was 63 years (range 14-89) and 62% were female. Meningioma WHO grades were 37% grade 1, 26.4% grade 2, 6.4% grade 3, and 30.2% imaging-defined. MMTB recommendations consisted of observation (36.3%), radiosurgery (38.4%), radiotherapy (27.4%), surgery (21.0%), systemic therapy (14.2% overall, 38.5% of WHO grade 2 or 3 meningiomas), and DOTATATE-PET (19.9%). Clinical trial enrollment was offered to 9.9% of patients, and prospective registry enrollment was offered to 83.6%. All patients were referred to neuro-oncology, 50.5% to radiation oncology, 18.9% to neurosurgery, and 29.5% to the UCSF MMDC (73.3% seen in consultation on the same day of MMTB). In summary, a tumor board and multidisciplinary clinic is a scalable model for coordinated meningioma care and research.

Abstract Myeloid-rich microenvironment is a hallmark of glioblastoma (GBM), the most aggressive and lethal brain malignancies in adults, leading to profound immunosuppression and therapy resistance. Metabolic dysregulation in tumor-associated myeloid cells (TAMCs) has been recognized as a key player driving immune evasion and supporting their pro-tumorigenic roles. Our single-cell RNA sequencing analysis and multiplex immunofluorescence have demonstrated high overexpression of monocarboxylate transporter 4 (MCT4), a key lactate transporter, in TAMCs in both murine and human GBMs, which may greatly contribute to TAMC-mediated GBM immunosuppression. To enable a myeloid-specific targeting of MCT4 in GBM, we have developed MCT4 nano-therapeutics using our antibody-directed immune targeting (ADIT) nano-platform. Lipid nanoparticles were surface functionalized with anti-PD-L1 antibody and encapsulated with small interfering RNA (siRNA) that targets MCT4. Our data indicated a robust and durable MCT4 inhibition, achieving over 90% gene knockdown efficiency. In vitro, MCT4 nano-therapeutics effectively targeted and reprogrammed immunosuppressive TAMCs, and restored CD8+ T cell proliferation and activation. In vivo, MCT4 nano-therapeutics through intracranial administration significantly improved the anti-glioma effectiveness of radiotherapy in CT-2A glioma-bearing C57 mice, leading to enhanced brain tumor infiltration of effector CD8+ T cells and CD103+ dendritic cells as well as much prolonged animal survival. When further combined with anti-CTLA-4 immune checkpoint therapy, over 60% of mice were cured from CT-2A glioma, and the long-term survivor animals developed anti-glioma immunological memory. Besides intracranial injections, we have also demonstrated the effectiveness of MCT4 nano-therapeutics through a systemic intranasal delivery route. These findings altogether may highlight a great potential of targeting lactate transport for modulating myeloid-mediated GBM immunosuppression and create a new immunotherapeutic approach to improve the existing standard treatments and immunotherapies for GBM.

Abstract INTRODUCTION To overcome immunosuppressive tumor microenvironment (TME) in GBM, our group developed ‘onion-like’ mRNA clusters in a microgel–chemokine matrix for enhanced immunogenicity. Instead of lipid particle localization to antigen presenting cells, this microgel-chemokine-mRNA (MCM) complex recruits dendritic and natural killer cells forming an ectopic Th1 lymph node necessary for educating and sustaining intra-tumoral immunotherapy. The objective of this study was to evaluate the effect of vaccine for GBM. METHODS C57BL/6 mice underwent intracranial implantation of KR158-luc tumor cells and underwent SQ injection of the MCM vaccine using total tumor mRNA. Tumors were harvested at defined time points for flow cytometry and transcriptomic profiling. Bulk RNA-seq was performed to characterize differential gene expression and pathway enrichment. Flow cytometry was done to evaluate the CCR5 expression (receptor for CCL4) in the TME. RESULTS MCM treatment significantly upregulated CCL4 within the tumor, and blockade of CCL4 abrogated the survival benefit conferred by the vaccine. Flow cytometry revealed that microglia in the TME had the highest expression of the CCR5 receptor. Bulk RNA-seq revealed a distinct transcriptional profile in the MCM-treated group, including enrichment of pathways related to T cell activation, cytokine signaling, and leukocyte migration. These findings suggest MCM drives adaptive immune activation and T cell migration in the TME. Gene ontology (GO) analysis indicated a shift toward M1-like microglial activation, with upregulation of pro-inflammatory mediators such as TNF, IL-6, and CD86. Next, QPCR on the isolated microglia from TME revealed MCM induces a pronounced shift toward the M1 pro-inflammatory microglial phenotype, characterized by increased expression of pro-inflammatory cytokine markers. CONCLUSION MCM treatment drives potent anti-tumor immunity in GBM by reprogramming microglia toward a pro-inflammatory phenotype and promoting T cell activation and infiltration within the TME.

Radiation therapy is the mainstay of therapy for patients with glioma. While this treatment modality can improve survival, treatment-related complications may include radiation-induced vasculopathy and increased risk of stroke. We aimed to evaluate the stroke frequency, associated risk factors, and outcomes after cranial radiation therapy in patients with glioma. This is a retrospective cohort study at a single tertiary academic brain tumor center involving patients diagnosed with gliomas between 2005 and 2021 who received cranial radiation therapy. Data were collected from the time of cranial radiation therapy until last follow-up. Logistic regression analyses were used to evaluate the association of clinical and demographic variables with all-cause, ischemic, and hemorrhagic strokes. In a retrospective cohort of 930 patients, 910 received radiation therapy (mean age 53.8 years; 40% women) and were included in the final analysis. A total of 91 patients (10.0%) were diagnosed with stroke (73.6% ischemic; 15.4% with recurrent strokes). The median time to diagnosis of stroke after onset of radiation therapy was 652 days with median time to recurrent stroke of 102 days. In a univariable model, Black race (odds ratio [OR] 3.83, 95% CI 1.94-7.56), radiation necrosis (OR 4.62, 95% CI 2.02-10.55), hypertension (OR 1.93, 95% CI 1.23-3.01), hyperlipidemia (OR 5.93, 95% CI 3.61-9.57), and diabetes mellitus (OR 2.25, 95% CI 1.28-3.95) were associated with higher odds of all-cause stroke. In multivariable analysis, Black race (OR 3.41, 95% CI 1.59-7.33), radiation necrosis (OR 6.42, 95% CI 2.45-16.79), and hyperlipidemia (OR 6.42, 95% CI 3.91-10.57) were significantly associated with increased odds of all-cause stroke. Radiation necrosis and hyperlipidemia were associated with increased odds of ischemic stroke. Black race, hyperlipidemia, and younger age were associated with increased odds of hemorrhagic stroke. Compared with ischemic strokes, hemorrhagic strokes were associated with higher poststroke disability. In a large, retrospective cohort of adult patients with glioma treated with cranial radiation therapy, 1 in 10 patients were subsequently diagnosed with stroke with 15.4% suffering recurrent strokes. Factors associated with increased odds of stroke included Black race, radiation necrosis, and hyperlipidemia and should be validated in future prospective cohorts. Study limitations include the retrospective design, incomplete stroke workups, and lack of molecular diagnostics.