tbuckley/cabot-search huggingface dataset:
TMIC-09. DENDRITIC CELL DYSFUNCTION RESTRICTS TUMOR ANTIGEN SPREADING IN ADOPTIVE CELLULAR TRANSFER THERAPY-ESCAPED GLIOMAS: IMPLICATIONS FOR TUMOR IMMUNE EVASION
Authors: Dan Jin
Journal: Neuro-Oncology (2024)

Abstract Dendritic cells (DCs) play a pivotal role in initiating anti-tumor immune responses. Our group has developed an adoptive cellular transfer therapy (ACT) that significantly increases the infiltration of DCs and T cells into tumors, markedly enhancing survival in murine brain tumor models. However, tumors develop mechanisms to restrict the immune surveillance and the efficacy of immunotherapy, leading to tumor escape. In this study, we identified a mechanism involving DC dysfunction in ACT-escaped brain tumors. The finding that DCs are enriched after ACT treatment prompts an investigation into whether DC function is impaired in ACT-escaped tumors. Our results showed that DCs from both primary and ACT-escaped tumors were dysfunctional in their ability to activate T cells when co-cultured with tumor-reactive T cells or OT1 T cells. RNA-seq data revealed that, compared to primary tumor DCs, ACT-escaped tumor DCs exhibited a more pronounced reduction in conventional DC markers and antigen-presenting genes, alongside increased tolerance markers. Gene set enrichment analysis indicated that epithelial-mesenchymal transition (EMT) and hypoxia pathways were significantly enriched in ACT-escaped tumor DCs, suggesting divergent DC dysfunction mechanisms in primary versus escaped tumors. The anti-tumor role of DCs is primarily exerted through the activation of tumor-reactive T cells. Therefore, we assessed the cytotoxicity and exhaustion status of T cells in tumors. Surprisingly, we found that T cells from ACT-escaped tumors exhibited significantly higher levels of cytotoxicity and lower levels of T cell exhaustion compared to primary tumors. This suggests a T cell exhaustion-independent mechanism in ACT-escaped tumors. We further demonstrated that T cells in ACT-escaped tumor are mainly sourced from the adoptive transferred T cells, which recognize primary tumor antigens but not escaped tumor antigens. These results suggest that a combined mechanism of tumor antigen shifting and impaired DC function leads to a failure of antigen spreading and tumor eradication.
TMIC-31. MOLECULAR PROGNOSTIC FACTORS OF THE PROGRESSION OF VESTIBULAR SCHWANNOMA AFTER PRIMARY TUMOR RESECTION
Authors: Ryo Mizuta, Keigo Makino, Yoshihiro Otai, Kentaro Fujii, Joji Ishida, Atsuhito Uneda, Nobushige Tsuboi, Shuichiro Hirano, Naoya Kemmotsu, Yasuki Suruga, Ryoji Imoto, Yasuhito Kegoya, Madoka Hokama, Ryosuke Ikemachi, Yuji Matsumoto, Yusuke Tomita, Yosuke Shimazu, Hirofumi Inoue, Yuanqing Yan, Ziyi Wang, Mitsuaki Ono, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Takao Yasuhara, Shota Tanaka
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Although vestibular schwannoma is a benign tumor, 10% of the tumor regrow after primary tumor resection. The factors associated with tumor progression from several reports remain controversial, and the role of the tumor microenvironment in vestibular schwannoma is still unclear. In this study, we analyzed the prognostic factors associated with the tumor progression after primary resection. METHODS We retrospectively reviewed the medical records of patients who underwent surgical resection and were diagnosed with vestibular schwannoma between January 2005 and June 2020. We performed RNA sequencing to identify the prognostic factors and immunohistochemistry to assess the tumor microenvironment, including analysis of the CD80 and CD206 expression of macrophages. We compared the progressed group whose tumor size got larger than 2mm after primary resection or who underwent additional treatment because of regrowth with the stable group. RESULTS Fifty-five patients underwent surgical resection for newly diagnosed vestibular schwannoma, and 12 of them had tumor regrowth. RNA sequencing revealed that the significantly upregulated pathways in the stable group was related to immune systems, while that of the progressed group was related to cell cycle. In addition, there were more myeloid cells, especially M2 macrophage infiltration in the stable group. Immunohistochemistry also showed higher M2 macrophages in the stable group. CONCLUSION In this study, multiomic analysis revealed the upregulation of immune-related pathways in the stable group and the cell cycle pathway in the progressed group. Altering the tumor microenvironment may offer a therapeutic strategy in vestibular schwannoma after primary resection.
EXTH-19. AN INTERNATIONAL ACCELERATOR PROGRAMME FOR RESEARCHERS DEVELOPING NOVEL THERAPIES FOR BRAIN TUMOURS
Authors: Charlotte Aitken, Nicky Huskens, Katie Bushby, Karen Noble, Petra Hamerlik, Edward Kaye, Dione Kobayashi, Ryan Mathew, John McCall, Javad Nazarian, Ruth Plummer, Ruman Rahman, Juanita Lopez, Kanneboyina Nagaraju
Journal: Neuro-Oncology (2024)

Abstract Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including robustness of preclinical studies, safety, clinical trial design, understanding and addressing regulatory requirements, and funding. Recognising the difficulty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pipeline. Supported by Brain Tumour Research, the BTR-NTA programme is free for academic applicants. Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants outline their current and prospective data and findings. The proposal and all supporting materials are covered under a confidentiality agreement that protects applicants’ intellectual property; 2. Proposals are reviewed by the BTR-NTA Committee; 3. Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre- and post-meeting. Since the launch of BTR-NTA in 2023,14 international groups have applied to the programme and seven therapies have been advanced to the in-person review by the BTR-NTA Committee. Of the applicants who provided feedback on the BTR-NTA programme, all intended to adjust or refine their future work based on the Committee’s input and the average rating of the programme’s helpfulness was 9.5 out of 10. The ultimate goal of BTR-NTA is to help researchers with a potential therapy for brain tumours to navigate the development journey and reach the clinic in an efficient way. This programme will support the development of novel therapies to improve outcomes for patients with brain tumours.
EXTH-53. THE PHARMACOLOGICAL ATLAS OF MENINGIOMAS
Authors: Gerhard Jungwirth, Yimin Pan, Derin Nalcakan, Rolf Warta, Amir Abdollahi, Andreas Unterberg, Sandro Krieg, Christel Herold-Mende
Journal: Neuro-Oncology (2024)

Abstract No systemic treatment options exist for recurrent or refractory meningioma patients. This study aimed to create a pharmacological atlas of all FDA-approved oncology drugs in a large cohort of patient-derived meningioma organoids (TOs). TOs were generated from single cell suspensions from freshly resected meningiomas and were treated with semi-logarithmic concentrations spanning from 10 nM to 30 µM by the automated liquid handler Hamilton MicroLAB STAR®. The drug library AODX from the National Cancer Institute consisted of 179 FDA-approved anticancer drugs. The viability was measured with the RealTimeGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. We created a pharmacological atlas of meningiomas by generating 8,413 dose-response curves of 179 current FDA-approved oncology drugs in patient-derived tumor organoids from 47 meningioma patients. The cohort consisted of 35 grade 1, 11 grade 2, and 1 grade 3 meningiomas, including 10 recurrent tumors. In total, 21% (n=39/179) of the drugs exhibited sensitivity (median IC50 &amp;lt; 30 µM), with significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine with median values of 10, 31, 145, 303, and 400 nM. Hierarchical clustering of IC50 data revealed at least two distinct drug response clusters defined by sensitivity to tyrosine kinase inhibitors. When considering the Cmax/IC50 ratio as a potential predictive marker of treatment response (&amp;gt;1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), the proteasome inhibitor carfilzomib (34.6), and the anthracyclines epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further in vivo evaluation. We provide the first comprehensive insight into the pharmacological landscape of meningiomas. This data might serve as the foundation for future clinical studies on the systemic treatment of aggressive meningiomas.
EPID-28. TRENDS IN LOW GRADE GLIOMA PROGNOSIS AND THE EVOLVING IMPACT OF GROSS TOTAL RESECTION ACROSS FIFTY YEARS: A MULTICOHORT ANALYSIS
Authors: Michael Jin, Jacob Young, Gray Umbach, Karthik Ravi, Michael Lim, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Significant advancements in neurosurgical planning, approach, and practice over the past five decades have improved the surgical management of diffuse low and high-grade gliomas. We sought to evaluate the extent to which LGG survival outcomes have evolved over the past fifty years using glioma registry datasets with histopathological groups defined by WHO diagnostic criteria and supplemented with next generation genome-sequencing. METHODS Three datasets (SEER, TCGA, and GENIE) were used to evaluate trends in prognosis following LGG diagnosis and resection between 1975 and present (GBM as a comparator cohort). The primary outcomes evaluated were longitudinal disease-specific survival and overall survival, with secondary fixed-timepoint outcomes evaluated at 12-months, 24-months, and 60-months. Subjects from SEER were categorized by histology, while subjects from TCGA and GENIE were included based IDH mutation status with available histopathology. RESULTS A total of 39,958 adult patients were included. Overall survival increased for both LGG and GBM between 1975 and 2010, however only LGG outcomes continued to improve following 2010 (2010-; HR=0.955, 95%CI 0.926 to 0.986). Evaluation of the interaction between resection extent and diagnosis year revealed a progressive increase in the survival benefit of GTR in recent years, particularly for LGG. Independent of other available clinical/molecular features and considering the interaction term between year of diagnosis and resection extent, the gap in independent prognostic benefit associated with GTR between LGG and GBM has significantly widened (2010-2020 vs 1990-2000, p&amp;lt;0.05). CONCLUSION Over the past three decades, consistent improvements in LGG outcomes were observed while prognosis following GBM diagnosis has remained largely unchanged following 2010. Notably, we observed increasing prognostic value of achieving GTR particularly in patients with LGG.
NIMG-87. MULTIREGIONAL, MRI-LOCALIZED SAMPLING OF HIGH GRADE GLIOMAS REVEAL SEX-DISTINCT PATTERNS OF 5-ALA FLUORESCENCE AND IMAGING FEATURES
Authors: Destiny Green, Pamela Jackson, Lee Curtin, Kyle Singleton, Michael Vogelbaum, Alfredo Quinones-Hinojosa, Bernard Bendok, Kristin Swanson
Journal: Neuro-Oncology (2024)

Abstract High grade gliomas (HGGs) are aggressive brain tumors that are difficult to remove completely, leading to poor survival rates. Contrast enhancement on T1Gd magnetic resonance imaging (MRI) has traditionally been used to guide resection, however it often underestimates true tumor burden, adding a layer of uncertainty for surgeons during pre-operative planning. Fluorescence guided surgery using 5-aminolevulinic acid (5-ALA) has emerged as an intraoperative solution and understanding it in conjunction with MRI features can address the limitations of routine T1Gd imaging during surgical planning. Here we investigate sex-specific patterns in HGGs using 5-ALA fluorescence and imaging features. We analyzed a patient dataset of 202 multiregional MRI-localized biopsies from 42 HGG patients (20 male and 22 female). Data included patient demographics, 5-ALA status (positive or negative), MRI annotations (CE = contrast enhancement, NE = non-enhancement, BAT = brain around tumor non-enhancement), and survival outcomes. Statistical analyses included Wilcoxon rank-sum tests, Kruskal-Wallis tests, and chi-squared tests to assess differences in imaging annotations and 5-ALA positive vs negative status among sex cohorts. Among all samples, CE and BAT were associated with higher 5-ALA positivity, while NE was associated with higher 5-ALA negativity (p = 0.02119). Female patients were less likely to have detectable 5-ALA in their multiregional biopsy samples than males (p &amp;lt; 0.0001). CE at the biopsy location was more likely to be indicative of 5-ALA positivity in males than females (p = 0.001927); whereas NE was associated with higher 5-ALA negativity in females than males (p = 0.03426). BAT was associated with higher 5-ALA positivity in males than females (p = 0.03895). Our study reveals sex-specific patterns in 5-ALA fluorescence and image features among HGG patients. These unique features may serve as potential pre-surgical markers for tumor regions that are more likely to benefit from 5-ALA-guided resection.
NCOG-35. IDENTIFYING PROGNOSTIC FACTORS IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS, H3 K27-ALTERED
Authors: Yufan Yang, Sachin Govind, Nitin Wadhwani, Daniel Brat, Roger Stupp, Sean Sachdev, Michael DeCuypere
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Diffuse midline gliomas, H3 K27-altered (DMG) are rare, grade 4 tumors localized to the diencephalon, brainstem, and cervical spine. DMGs, characterized by a K27M missense mutation in histone H3, often cannot be safely resected and predominantly present with poor outcomes in children. Few prognostic factors for DMGs have been identified and/or need to be further elucidated, including adolescent age of onset, re-irradiation status, and tumor molecular profile (i.e., PIK3CA mutation). Herein, we describe the clinical outcomes of DMG patients at our institution. METHODS Pediatric patients (&amp;lt;18 y/o) between 2015 and 2023 with biopsy-proven DMG were reviewed. Demographic, treatment, and tumor characteristics (histologic and molecular) were recorded. Adolescent-onset DMGs were defined as patients ≥10 y/o at diagnosis and early-onset DMGs were defined as patients &amp;lt;10 y/o. Progression free survival (PFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Multivariate regression analyses were performed. RESULTS Twenty-one patients were included (median age=9 y/o). Early-onset DMGs (n=13) progressed significantly earlier and experienced significantly greater mortality than adolescent-onset DMGs (n=8); PFS and OS at 12 months was 7.7% and 23% for early-onset DMGs and 50% and 87.5% for adolescent-onset DMGs (PFS: p&amp;lt;0.01, OS: p&amp;lt;0.02). Patients that received re-irradiation for progressive disease (n=9, mean=84Gy) had an OS of 75% at 12 months, which was significantly greater than an OS of 23% at 12 months (p&amp;lt;0.05) for patients that received no re-irradiation (n=12, mean=53Gy). PIK3CA mutation status was identified as an independent predictor of survival, with PIK3CA-mutant DMGs (n=7) having a median survival of 4.1 months versus 9.7 months for PIK3CA-WT DMGs. CONCLUSION We describe a pediatric cohort that presents several possible prognostic factors of survival in DMGs. Our findings on adolescent age of onset, if further corroborated, has the potential to inform the design and enrollment of DMG clinical trials.
TMOD-14. ESTABLISHING A CLINICALLY RELEVANT MOUSE MODEL TO STUDY NECROSIS AS A PRIMARY VARIABLE IN GLIOBLASTOMA
Authors: Jiabo Li, Ling-kai Shih, Steven Markwell, Cheryl Olson, David Sullivan, Nicholas Lam, Daniel Brat
Journal: Neuro-Oncology (2024)

Abstract All glioblastoma (GBM) molecular subsets share the common trait of accelerated progression following necrosis, which cannot be adequately explained by cellular proliferation arising from accumulated genetic alterations. We suggest that necrosis is much more than a passive phenomenon related to rapid growth but rather is a driving force causing tumor microenvironment (TME) restructuring and biologic progression. yet mechanisms remain poorly understood due to a lack of animal models to study necrosis as a primary variable. In GBM, the most malignant primary brain tumor, vascular pathology and central necrosis precede rapid, radial expansion. To reveal spatio-temporal changes directly following vascular damage in the brain, we developed methodology to induce clinically relevant thrombosis vaso-occlusion within GBMs in immunocompetent RCAS/tv-a mouse model to study TME restructuring by intravital microscopy and demonstrate its impact on glioma progression in real-time. We found that following Rose Bengal photothrombosis, GBMs rapidly expanded radially, with glioma migration away from central necrosis and tumor-associated macrophages (TAMs) and glioma stem cells (GSCs) increased dramatically in the peri-necrotic zones. Through the single cell tracking analysis, we found that TAMs displaying increased displacement toward necrosis and greater overall migration distances. Collectively, this model introduces necrosis as the primary variable and captures glioma growth dynamics and TME restructuring in a manner that will facilitate the development of therapies that antagonize these mechanisms to improve outcomes.
TMOD-01. EGFR AMPLIFICATION ACCOMPANIES ADAPTATION TO MITOGEN-INDUCED DEFECTIVE MITOSIS IN PDGFA
Authors: Mathieu Meode, Hiba Omairi, Sarah Sait, Sophie Black, J Gregory Cairncross
Journal: Neuro-Oncology (2024)

Abstract Using a newly described in vitro murine model of GBM [Bohm et al., Neuro-Oncol 2020 and Omairi et al., Neuro-Oncol 2023] in which P53 null neural progenitor cells (NPCs) divide abnormally and evolve a GBM-like genome during exposure to Platelet-Derived Growth Factor-AA (PDGFA), we asked how a brain-abundant mitogen could transform NPCs. By analyzing gene and protein expression over time, we found that PDGFA fails to induce the transcription of kinetochore and spindle assembly checkpoint genes, while simultaneously driving NPCs to enter mitosis. These dual effects caused chromosome miss-segregation in continuously dividing NPCs; moreover, they occurred in both WT and null NPCs, although only null cells survived defective mitosis. These surviving cells gradually expanded in PDGFA accumulating both random and clonal chromosomal re-arrangements. Transcriptome analysis of NPCs in PDGFA revealed significant under-expression of Foxm1, the major regulator of kinetochore transcription, together with over-expression and phosphorylation of the immediate early response gene, FOS. Analysis of signalling downstream of PDGFRα identified the Ras-MAPK pathway, especially ERK, as responsible for FOS activation. As surviving null cells gradually expanded, they accumulated random and recurrent chromosomal rearrangements. Expansion and subsequent PDGFA-independent proliferation and tumorigenicity were associated with re-expression of Foxm1 and kinetochore proteins, and accompanied by over-expression of Egfr, an RTK-signature that defines human GBM. By stimulating proliferation without setting the stage for error-free mitosis, exposure to PDGFA transforms p53 null NPCs and generates Egfr amplified GBM-like cancer cells.
TMIC-26. IMMUNE CELL DYNAMICS WITHIN GLIOMAS: THE INFLUENCE OF GRADE AND IDH STATUS
Authors: Eric P Grewal, Leland GK Richardson, Jing Sun, Rishab Ramapriyan, Maria Martinez-Lage, Julie J Miller, Bob S Carter, Daniel P Cahill, William T Curry, Bryan D Choi
Journal: Neuro-Oncology (2024)

Abstract Mutations in isocitrate dehydrogenase (IDH) are known to significantly impact the prognosis and biology of diffuse gliomas. A number of studies have compared the immune microenvironment of IDH-wildtype glioma versus IDH-mutant glioma, and have also characterized the impact of mutant-IDH on lymphocytes. However, few studies have explored how mutant-IDH may affect tumors as they progress and increase in grade, or have delved into the myeloid immune cell compartment. Thus, we sought to understand whether tumor progression affected intratumoral immune cell composition within IDH-mutant glioma, and aimed to compare IDH-mutant versus IDH-wildtype glioma in both humans and mice. Using bulk RNA sequencing, we compared paired samples from patients with IDH-mutant glioma before and after progression, focusing on differentially-expressed immunological genes and relative immune cell proportions. We also compared grade 4 IDH-mutant astrocytoma cases to IDH-wildtype glioblastoma, performing both transcriptomic and cellular analyses. Finally, we engineered murine glioma cells to test the effect of mutant-IDH alone in the tumor microenvironment. We found that multiple immune-related genes distinguish low- and high-grade IDH-mutant glioma, and that high-grade tumors contain greater proportions of suppressive myeloid cells. When comparing IDH-wildtype to IDH-mutant glioma, we found enrichment of suppressive macrophages and myeloid-derived suppressor cells (MDSC) in IDH-wildtype tumors. Finally, our murine model of IDH-wildtype versus IDH-mutant glioma mirrored many of the myeloid cell shifts observed in human tumors. Our data show that progression of IDH-mutant tumors is a significant immunological phenomenon, associated with marked alterations in the tumor immune microenvironment. We also show that IDH-mutant glioma harbors greater inflammatory signatures and fewer suppressive myeloid cells than IDH-wildtype glioma, and that engineering mutant IDH into murine tumors is sufficient to model these differences. These findings improve our understanding of key intratumoral cell populations that may be harnessed by future immunotherapeutic strategies.