Citations

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Abstract INTRODUCTION Glioblastoma (GBM) contains metabolically distinct cell lineages: treatment-sensitive cells (TSCs) dependent on glycolysis and treatment-resistant persister cells (TRPCs) reliant on lipid metabolism. Our integrative systems biology approach, combining spatial multi-omics and targeted analyses, uncovers lipid acquisition in TRPCs as a pivotal driver of GBM progression which is supported by a retrospective study of statin-treated patients, providing clinical evidence for the therapeutic potential of targeting lipid metabolism in GBM patients stratified based on high TRPC signatures. METHODS We applied spatial transcriptomics and proteomics combined with 3D reconstruction of the tumor microenvironment to map TRPC- and TSC-enriched regions. Immunohistochemically stained tissues were analyzed using CellProfiler and our custom SNAQ algorithm for single-cell neighborhood analysis. Lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs was tracked via flow cytometry, holotomography, and time-lapse imaging. Genetic and pharmacological targeting of CCR2, CSF1R, and FABP3 was performed in vitro and in vivo. Finally, a retrospective analysis of 4,085 GBM patients assessed the impact of statin treatment in relation to TRPC signatures. RESULTS TRPCs exploit recruited TAMCs to acquire lipids, supporting their survival and immune evasion. These interactions are mediated by CCL2/7–CCR2 and CSF1–CSF1R signaling. Disruption of TRPC-TAM lipid homeostasis significantly remodeled the immune microenvironment, reduced tumor growth, and extended survival in preclinical models. Patients with high TRPC signatures typically had poor outcomes; however, retrospective analysis revealed that statin treatment was associated with improved survival in this subgroup. These findings position lipid trafficking as a metabolic vulnerability in GBM and highlight the therapeutic relevance of targeting TRPC–TAMC interactions. CONCLUSION Our study reveals lipid trafficking to TRPCs as a key mechanism driving GBM progression. Targeting TAMC-mediated lipid transfer disrupts immune suppression and tumor growth. Transcriptomic profiling may guide patient stratification, identifying those likely to benefit from lipid metabolism-targeted therapies such as statins.

Abstract INTRODUCTION Glioblastoma (GBM) is a brain cancer known for its complex tumor microenvironment and ability to reprogram glucose metabolism and evade host immune responses. CAR-T cell therapy has attracted considerable attention due to its potential for high specificity and efficacy across various cancer types. However, its success in GBM has been limited due to the unique and hostile metabolic landscape of the tumor microenvironment. GBM tumor cells exhibit enhanced aerobic glycolysis, resulting in elevated glucose consumption. This restricts glucose availability for T cells, impairing activation and anti-tumor response. In our study, we enhanced the tumoricidal activity of CD70 CAR T-cells by overexpressing the glucose transporters GLUT1 and GLUT3, thereby improving their metabolic fitness and enabling them to overcome tumor-induced glucose deprivation. METHODS The CD70 CAR T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The efficacy and safety of metabolically modified CD70 CAR T-cells was investigated in in vitro and in vivo platforms. RESULTS GLUTs overexpression does not negatively affect T-cell differentiation and function but improves glucose consumption and intra-tumoral T-cell trafficking. We then used CD70 CAR-T platform and overexpress GLUT1 and GLUT3 to engineer T-cells. GLUT overexpression provided metabolic advantage to CD70CAR T-cells, which showed enhanced activation and cell avidity when co-cultured with GBM cells in both glucose enriched and restricted conditions. The metabolic modifications regulate CAR T-cell efficacy by enhancing intra-tumoral trafficking and persistence, followed by improved anti-tumor response and survival in mice. The lack of significant alterations in body weight and organ morphology in mice receiving GLUT-overexpressing CD70 CAR T-cells suggests that the adoptive transfer of these metabolically enhanced T cells does not elicit toxicity, thereby demonstrating a favorable safety profile during treatment. CONCLUSION Our study demonstrates development of immunotherapeutic strategies by incorporating core principles of tumor and immune cell metabolism, thus providing evidence that targeting immune-metabolic pathways is a potential approach to treat brain tumor.

Abstract Immune checkpoint inhibitors (ICIs) have limited benefit in recurrent high-grade astrocytoma (rHGA), largely because the blood–brain barrier and a profoundly immunosuppressive tumor microenvironment prevent T cells from infiltrating. Laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive procedure that can “heat up” these otherwise “cold” tumors and sensitize them to ICIs. In this tri-institutional Phase 1/randomized Phase 2 trial (NCT02311582), bevacizumab- and immunotherapy-naïve rHGA patients were initially randomized 1:1 to either LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). Phase 2 participants enrolled at a second recurrence—with several already at a third recurrence—underscoring the advanced disease stage of this cohort. After 21 patients, randomization was halted when contemporaneous evidence showed limited benefit from adjuvant ICIs alone, and the remaining 24 patients received only LITT+PEM. In the 21-patient intent-to-treat cohort, LITT+PEM extended median OS to 21.3 months with 54% alive at 18 months (OS18) versus 6.7 months with 12.5% OS18 with NLS+PEM (HR 0.29; 95% CI, 0.01–0.88; p=0.021). Median PFS was 7.8 versus 2.2 months (HR 0.3; 95% CI, 0.10–0.87; p=0.020). Among 39 per-protocol patients, LITT+PEM yielded a median OS of 11.8 months with 42% OS18 versus 5.2 months with 0% OS18 for NLS+PEM (HR 0.17; 95% CI, 0.06–0.49; p=0.0002), and a median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of non-classical monocytes—a change associated with improved survival—while subsequent pembrolizumab unleashes robust CD8⁺ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes. Together, these results demonstrate that LITT plus pembrolizumab is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.

Abstract Introduction: Glioblastoma (GBM) tumors contain distinct cell lineages, including treatment-sensitive cells (TSCs) relying on aerobic glycolysis and treatment-resistant persister cells (TRPCs) dependent on lipid metabolism. Our systems biology-based, spatial multi-omics and multi-targeted approach decodes a critical node in GBM progression, lipid acquisition in TRPCs, and validates this through a retrospective analysis of statin-treated patients, offering clinical insights into the potential benefits of targeting lipid metabolism in high TRPC signature GBM patients. Methods: We performed spatial transcriptomics and proteomics, combined with 3D rendering of the tumor microenvironment (TME) and geospatially resolved single-cell neighborhood analysis of IHC-stained GBM tissues using our custom-developed SNAQ algorithm to investigate the immune microenvironment and lipid distribution specific to TSCs and TRPCs. To characterize lipid dynamics, we employed flow cytometry, time-lapse imaging, and holotomography to track lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs. A critical node for GBM progression was identified through in vivo survival and tumor progression studies that assessed effects of genetic targeting of CCR2 and pharmacological targeting of CSF1R and FABP3. Retrospective analysis was conducted on 4,085 GBM patients to evaluate the effect of statin treatment on GBM outcomes based on their TRPC signature. Results: Our study establishes the skewed accumulation of TAMCs within the TRPC microenvironment through upregulation of the CCL2/7-CCR2 and CSF1-CSF1R pathways. TAMCs actively transfer lipids to TRPCs to fulfill their metabolic demands. Targeting elements responsible for lipid incorporation in TRPCs, such as CCR2, CSF1R, and FABP3 in vivo, resulted in tumor immune microenvironment remodeling, significant tumor growth reduction, and improved survival. This reinforces the critical role of metabolic communications via lipid trafficking in TRPCs as an essential node in GBM progression. Our retrospective study showed that GBM patients with elevated TRPC signatures, typically associated with shorter survival, had no significant survival differences when treated with lipid-lowering statins. This suggests statins may disrupt lipid metabolism in TRPCs, reducing TAMC lipid support and improving patient outcomes. Conclusion: Our study highlights lipid trafficking in TRPCs as a key mechanism in GBM progression, suggesting that targeting TAMC recruitment and lipid acquisition in TRPCs may offer a promising therapy. Additionally, our retrospective analysis highlights the potential of transcriptomic profiling for patient stratification based on TRPC signature expression levels, enabling the identification of patients to benefit from lipid metabolism-targeted therapies. Citation Format: Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Nyla T. Searl, Miruna Anica, Avinash Pittu, Illena West, Olusegun O. Sobanjo, Ethan D. Hodge, Mia K. Engelbart, Srabasti Sengupta, Nagheme Thomas, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane A. Mitchell, Loic P. Deleyrolle. Disrupting lipid metabolism in GBM: A systems biology approach to targeting treatment-resistant persister cells and tumor associated myeloid cell-mediated support [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB082.

Abstract Meningiomas are the most common primary intracranial tumor. They are slow growing and often incidentally found tumors that arise from the arachnoid villi. As they grow, they have a greater likelihood of becoming symptomatic with seizures being one of the most clinically significant symptoms. Seizures are more likely to present as a symptom of larger meningiomas and meningiomas that compress cortical areas particularly those in non-skull base locations. These seizures are often managed medically, utilizing the same anti-seizure medications that are used to treat other causes of epilepsy. We discuss common anti-seizure medications used including valproate, phenobarbital, carbamazepine, phenytoin, lacosamide, lamotrigine, levetiracetam and topiramate and their common adverse effects. The goal of pharmacotherapy for seizure control is to maximize seizure control while minimizing the adverse effects of the medication. The decision to provide medical management is dependent on individual seizure history and plans for surgical treatment. Patients who did not require seizure prophylaxis before surgery are commonly prescribed seizure prophylaxis postoperatively. Symptomatic meningiomas not controlled by medical management alone are commonly evaluated for surgical resection. The efficacy of surgical resection in providing seizure freedom is dependent on several features of the tumor including tumor size, the extent of the peritumoral edema, the number of tumors, sinus infiltration and the degree of resection.