tbuckley/cabot-search huggingface dataset:
DISP-16. EXPLORING SEX-BASED DIFFERENCES IN RESPONSE TO IMMUNOTHERAPY IN GLIOBLASTOMA: A RETROSPECTIVE REVIEW
Authors: Catharina Westergaard, Vihang Nakhate, Aleksandra Beata Lasica, Alona Muzikansky, Brooke Barlow, Alyssa Russ, Chibueze Nwagwu, Eudocia Lee, Ugonma Chukwueke, Lakshmi Nayak, Luis Nicolas Gonzalez Castro, Jose Ricardo McFaline Figueroa, Elisa Aquilanti, Rameen Beroukhim, Tracy Batchelor, David Reardon, Patrick Wen, Gilbert Youssef
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The prognostic implication of sex is unclear in glioblastoma. A recent preclinical study suggested that T-cell exhaustion in males confers improved response to anti-PD1 therapy (PMID: 37378557). We conducted a retrospective study of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma enrolled on immunotherapy trials at Dana-Farber Cancer Institute from 2014 to 2022 to determine whether sex influences the response to immunotherapy. METHODS Clinical, molecular, and radiographic data were collected, and their association with progression-free survival (PFS) and overall survival (OS) was evaluated using log-rank. RESULTS We evaluated 299 subjects with nGBM (172 male, 127 female) and 539 with rGBM (329 male, 210 female). In the nGBM cohort, median PFS for males vs females was 9.1 [7.2, 13.8] months vs 8.8 [6.5, 10.1] months (p=0.59) among subjects on immunotherapy trials (N=106), and 6.9 [6.1, 8.0] vs 6.5 [5.8, 8.1] months (p=0.44) in those on non-immunotherapy trials (N=193). Median OS was 18.6 [15.4, 24.0] in males vs 18.8 [15.9, 23.1] months in females (p=0.85) in immunotherapy trials and 15.6 [14.7, 17.3] vs 15.3 [13.1, 16.9] months (p=0.77) in non-immunotherapy trials. There was also no statistically significant difference in OS and PFS between sexes in the rGBM cohort: median PFS was 3.6 [3.0, 4.1] months in males vs 4.1 [3.8, 5.2] months in females and median OS was 8.4 [7.4, 9.6] vs 9.6 [8.2, 12.1] months in immunotherapy trials (N=254); median PFS was 1.8 [1.7, 2.1] vs 1.9 [1.8, 2.4] months and median OS was 8.6 [7.5, 9.6] vs 8.5 [7.3, 9.6] months in non-immunotherapy trials (N=285). CONCLUSION Sex did not have a prognostic impact on survival outcomes, regardless of the treatment modality. The impact of other clinical variables such as corticosteroid use, performance status, lymphocyte counts, and tumor burden will be reported.
NCOG-39. EXPLORING THE POTENTIAL OF STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF MENINGIOMAS
Authors: Greta Sallese, Anuttham Kandhadai, Paul Brindley
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Meningiomas present complex therapeutic challenges due to their potential impact on neurological function and quality of life. While the standard of care involves observation and surgical resection, stereotactic radiosurgery (SRS) is an alternative treatment modality. This study aimed to compare the relative efficacy of SRS and surgical resection in the management of meningiomas to inform evidence-based decision-making in this clinical context. METHODS A retrospective cohort study was conducted using the TriNetX database, comparing patients undergoing treatment for meningiomas with either stereotactic radiosurgery (SRS) or surgical resection. Cohorts were matched on comorbidities. Rates of mortality and malignant neoplasms of the brain within 5-years of treatment with either modality were compared. In addition, short-term outcomes were assessed at 3 months post-treatment. RESULTS After matching, there were 1,898 patients in each cohort. Patients receiving SRS exhibited a significantly lower risk of mortality (95% CI: 0.76-1.07) and a decreased risk of developing malignant neoplasms of the brain (RR: 0.68, 95% CI: 0.54-0.85) over 5 years, compared to surgical resection. At 3-months post treatment, patients treated with SRS demonstrated significantly lower relative risks for several outcomes, including cerebral infarction (RR: 0.27, 95% CI: 0.18-0.39), hydrocephalus (RR: 0.19, 95% CI: 0.11-0.32), cerebral edema (RR: 0.13, 95% CI: 0.10-0.18), seizures (RR: 0.27, 95% CI: 0.21-0.34), neurological deficits (RR: 0.19, 95% CI: 0.13-0.28), and post-procedural infection (RR: 0.14, 95% CI: 0.07-0.28). CONCLUSION This retrospective cohort study suggests that in the management of meningiomas, SRS may be associated with lower mortality rates, decreased risks of malignant neoplasms of the brain, and improved short-term outcomes compared to surgical resection. Further research is warranted to validate these results and explore long-term outcomes and potential adverse effects.
QOL-17. REFLECTIONS ON A PSYCHOEDUCATION INTERVENTION FOR PATIENTS WITH NEWLY DIAGNOSED BRAIN TUMORS (NEUROPATHWAYS): A QUALITATIVE STUDY
Authors: Jessica Whitman, Sumita Strander, Alyx Podgurski, Kelcie Willis, Daniel Chiu, Michael Parsons, Amy Maguire, Sarah Steele, Christopher Curtis, Kara Warner, Joelle McCone, Jennifer Temel, Lara Traeger, Deborah Forst
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with newly diagnosed primary malignant brain tumors (PMBT) face unique challenges processing and absorbing information regarding their diagnosis, often while contending with cognitive and communication deficits. Limited research exists regarding optimal information provision and support for this highly distressed population. We used input from clinician, patient, and caregiver stakeholders to design a population-specific, psychoeducation intervention (“NeuroPathways”) to address these needs. METHODS We conducted a single-arm study (N=12) to pilot and refine NeuroPathways in English-speaking patients within six-weeks of a PMBT diagnosis. Neuropathways comprises 1) a comprehensive (105 pages) handbook covering information about PMBT diagnosis, treatment, coping, self-care, and vetted resources, and 2) four brief, individual telehealth sessions with a trained interventionist (e.g., psychologist, physician) over 4-8 weeks to assist and empower patients to obtain information, support, and coping guidance at their preferred depth and pace, using the handbook as a resource. Ten participants completed all four sessions and participated in semi-structured exit interviews. We used rapid qualitative analysis to explore participants’ perceptions of intervention delivery, content, and benefit. RESULTS Participants (83% male, median age=52 years) uniformly described NeuroPathways as accessible, citing the telehealth format as particularly important for facilitating participation given logistical challenges related to cancer treatment. Perceived benefits of participation included: a) access to well-organized information targeting both current and future disease- and treatment-related concerns; b) increased skill in problem solving and communication with loved ones and/or medical providers; c) personalized emotional support from interventionists. While most felt the timing was appropriate, several who enrolled later in the eligibility window stated a desire for earlier intervention. CONCLUSION Participant feedback highlights the accessibility and potential benefits of this psychoeducation intervention for patients with newly diagnosed PMBT. These data will inform refinement of NeuroPathways in preparation for a pilot randomized controlled trial to formally assess feasibility and acceptability.
NCOG-37. SINGLE CENTER EXPERIENCE OF IDH INHIBITORS IN THE TREATMENT OF RECURRENT HIGH GRADE GLIOMAS
Authors: Catherine Garcia, Kaitlin Highsmith, Stephanie Knight, Vinay Puduvalli, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The antitumor effect of IDH inhibitors in high grade gliomas (HGG) is not well known, with conflicting views regarding the role of IDH status and the potential for resistance to DNA damage treatments. We present the outcomes of patients with HGG that were treated with IDH inhibitors at our institution. METHODS We performed a retrospective review of patients with IDH mutant gliomas treated with FDA approved IDH inhibitors (ivosidenib and enasidenib) in the past 5 years at our institution. One cycle of IDH inhibitor was defined as treatment for 28 days. RESULTS We identified 10 HGG patients (both oligodendrogliomas and astrocytomas). Median age at diagnosis was 31 years and 7 were male. Seven patients were diagnosed as WHO grade 3. Six patients were WHO grade 3 oligodendrogliomas, three WHO grade 4 astrocytomas, and one patient WHO grade 3 astrocytoma. Only one patient received enasidenib and the rest were treated with ivosidenib. Eight patients were started on IDH inhibitors after 3 recurrences. Median number of cycles was 5. One patient received 23 cycles, and one patient received 11 cycles. All patients underwent resection, 4 received chemotherapy (including temozolomide, bevacizumab, and CCNU), and 4 radiation prior to starting IDH inhibitors. One patient was treated with Tumor Treating Fields. Five patients progressed during the study follow up, and 3 patients died. Four patients are still on treatment. No serious adverse events. Median PFS after starting an IDH inhibitor was 6 months. DISCUSSION IDH inhibitors were well tolerated in IDH mutant HGG patients previously treated with DNA-damaging agents. It may have a role in the treatment of HGG with multiple recurrences with 3 patients showing stable disease for more than 18 months. More studies are needed to clarify the role of IDH inhibitors in patients with IDH mutant HGG.
TMIC-68. DEEP LEARNING OF THE SPATIAL IMMUNE ENGAGEMENT IN GLIOBLASTOMA UNDER TEMOZOLOMIDE TREATMENT
Authors: Simon Castillo, Afrooz Jahedi, Pravesh Gupta, Jason Huse, Kasthuri Kannan, Yinyin Yuan, Krishna Bhat
Journal: Neuro-Oncology (2024)

Abstract Effective immune synapses are a prerequisite for desirable immune surveillance and control of tumour growth. Cell-to-cell interactions form the basis of immune synapses, resulting in either immunoprotected or immunosuppressed manifestations in the tumour brain that could explain glioblastoma (GBM) recurrence. Using state-of-the-art multiplex imaging, spatial statistics, and spatially aware deep learning tools in 14 patient-matching tissues from primary and recurrent GBM, we detected spatial immune networks (SINets). SINets across 105 regions of interest comprising 2.3 million cells show stronger spatial engagement between myeloid and lymphoid lineages at recurrence. SINets’ architecture in primary tumours is associated with relapse timing. Patients, where the SINets are more modular, recur sooner than patients with denser SiNets. In addition, this association presents sexual dimorphism in our cohort (N=3 females, and N=4 males). Phenotype-to-phenotype spatial coexistence also contributes to enhancing phenotype prediction. A spatial-aware deep learning model trained with single-cell data from primary tumours reaches an average balanced accuracy of 0.76 in primary tumour cellular communities unseen during training, compared to a spatial-agnostic model that reached an average balanced accuracy of 0.69. In summary, we detected a distinct spatial engagement in glioblastoma undergoing chemo-radiation treatment. The spatial patterns of coexistence represent ecological niches that contribute to defining cell occurrence and may underpin effective immune synapses. Overall, the spatiotemporal elements provide a newer approach for dissecting glioblastoma’s complexity and discovering opportunities for stratifying patients by harnessing spatial information encoded in multicellular niches.
EXTH-68. EPIGENETIC EDITING BY MRNA-BASED CRISPROFF ENABLES FLEXIBLE AND DURABLE TARGETING OF GLIOBLASTOMA DRIVERS MGMT AND TERT
Authors: Katie Lin, Christopher Zou, Laine Goudy, Rohit Sharma, Nicholas O Stevers, Joanna Pak, Kyla Foster, Emily Payne, Anny Shai, Tomoko Ozawa, John F de Groot, Harish Vasudevan, Joanna J Phillips, David R Raleigh, Joseph F Costello, Niren Murthy, Luke A Gilbert, Mitchel Berger, S John Liu
Journal: Neuro-Oncology (2024)

Abstract Alterations in cis-regulatory elements, such as hypomethylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and activating mutations within the telomerase reverse transcriptase (TERT) promoter, are pervasive drivers of glioblastoma (GBM) tumorigenesis that are challenging to target. CRISPRoff is an engineered CRISPR/Cas9 system that can potently and heritably silence cis-regulatory elements through DNA methylation. Here, we develop an mRNA-based CRISPRoff platform to target the MGMT and TERT promoters in GBM, and we establish proof-of-principal in vivo targeting through lipid nanoparticles (LNP). Epigenetic editing in GBM cells and primary GBM organoids was performed using either electroporation or LNP encapsulation of CRISPRoff mRNA and sgRNAs. Target gene silencing and functional phenotypes were assessed by bisulfite sequencing, RT-qPCR, RNA-seq, western blot, cell viability/apoptosis, and telomere restriction fragment assays. In vivo efficacy was demonstrated using intracranial GBM xenografts, first through transplantation of cells with CRISPRoff delivered ex vivo, then with direct delivery of LNPs using convection enhanced delivery (CED) coupled with immunofluorescence/ immunohistochemistry. CRISPRoff targeting of MGMT promoter resulted in &amp;gt;99% reduction in MGMT expression in MGMT unmethylated primary GBM organoids, inducing up to 150-fold sensitization to temozolomide. Temozolomide sensitization was retained after intracrania transplantation, and silencing was durable in clonally isolated GBM cells continuously passaged for over 8 months after transient delivery of CRISPRoff. CRISPRoff targeting of the TERT promoter in primary GBM cultures harboring the G228A TERT promoter mutation silenced TERT expression by up to 99%, overcoming constitutive activation of TERT, and induced telomere shortening sufficient for complete replicative senescence. CED of mRNAs encapsulated by LNPs based on cKK-E12 or Lipid A9 resulted in tumor-selective uptake of mRNA transcripts, establishing a foundation for direct delivery of CRISPRoff in vivo bypassing the blood-brain-barrier. In summary, we establish a flexible and durable epigenetic editing system against multiple regulatory elements driving GBM, leveraging LNPs with potential for in vivo application.
DNAR-01. THERAPEUTIC APPLICATIONS OF MESENCHYMAL STEM CELL LOADED WITH GOLD NANOPARTICLES FOR REGENERATIVE MEDICINE
Authors: Wen-Yu Cheng, Meng-Yin Yang, Chun-An Yeh, Yi-Chin Yang, Chiung-Chyi Shen, Huey-Shan Hung
Journal: Neuro-Oncology (2024)

Abstract In the present study, the various concentrations of AuNP (1.25, 2.5, 5, 10 ppm) were prepared to investigate the biocompatibility, biological performances and cell uptake efficiency via Wharton’s jelly mesenchymal stem cells and rat model. The pure AuNP, AuNP combined with Col (AuNP-Col) and FITC conjugated AuNP-Col (AuNP-Col-FITC) were characterized by Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic Light Scattering (DLS) assays. For in vitro examinations, we explored whether the Wharton’s jelly MSCs had better viability, higher CXCR4 expression, greater migration distance and lower apoptotic-related proteins expression with AuNP 1.25 and 2.5 ppm treatments. Furthermore, we considered whether the treatments of 1.25 and 2.5 ppm AuNP could induce the CXCR4 knocked down Wharton’s jelly MSCs to express CXCR4 and reduce the expression level of apoptotic proteins. We also treated the Wharton’s jelly MSCs with AuNP-Col to investigate the intracellular uptake mechanisms. The evidence demonstrated the cells uptake AuNP-Col through clathrin-mediated endocytosis and the vacuolar-type H+-ATPase pathway with good stability inside the cells to avoid lysosomal degradation as well as better uptake efficiency. Additionally, the results from in vivo examinations elucidated the 2.5 ppm of AuNP attenuated foreign body responses and had better retention efficacy with tissue integrity in animal model. In conclusion, the evidence demonstrates that AuNP shows promise as a biosafe nanodrug delivery system for development of regenerative medicine coupled with Wharton’s jelly MSCs.
PATH-63. M6A REGULATOR-BASED MOLECULAR CLASSIFICATION AND HUB GENES ASSOCIATED WITH IMMUNE INFILTRATION CHARACTERISTICS AND CLINICAL OUTCOMES IN DIFFUSE GLIOMAS
Authors: Jie Lu, Siyu Chen, Depei Li, Yonggao Mou
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND m6A methylation modification is a new regulatory mechanism involved in tumorigenesis and tumor-immunity interaction. However, its impact on glioma immune microenvironment and clinical outcome remains unclear. METHODS Comprehensive expression profiles of 18 m6A regulators were used to identify molecular subtypes exhibiting distinct m6A modification patterns in 1673 glioma samples sourced from public datasets. A multi-genes signature was constructed for predicting clinical outcome and response to immunotherapy in glioma patients. Immunohistochemistry and cellular experiments were performed for validation. RESULTS Two m6A subtypes of gliomas were identified. The m6A-low-risk subtype was characterized by paucity of immune infiltrates; Whereas the m6A-high-risk subtype had higher abundances of multiple immune cells including lymphocyte and macrophage as well as increased expression of PD-L1, corresponding to an immunosuppressive phenotype. The m6A-high-risk subtype had poorer survival than the m6A-low-risk subtype in both the glioblastoma and lower grade gliomas cohorts. Eight m6A-related hub genes of high prognostic significances were identified and selected for developing a scoring signature termed as m6Ascore. Elevated m6Ascore indicated worse survival for glioma patients under standard care, but showed enhanced response to immunotherapy. Moreover, we demonstrated that overexpression of FTO, a m6A demethylase, inhibited the expressions of m6A-related hub genes (PTX3, SPAG4), impaired glioma cell viability and reduced macrophage chemotaxis. CONCLUSION This work develops an immune- and clinical-relevant m6A subtyping and a scoring model, which enhances our understanding of the role of m6A modification in regulating immune infiltration microenvironment in gliomas and helps to identify patients who are more likely to benefit from immunotherapy.
IMMU-10. IDENTIFICATION OF A NEW THERAPEUTIC ANTIGEN FOR GLIOBLASTOMA USING A MONOCLONAL ANTIBODY LIBRARY FROM PATIENT-DERIVED TUMOR SPHERES
Authors: Hideki Kuroda
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new treatment strategies are urgently needed. Various innovative cancer therapies targeting cancer-specific cell surface antigens, such as chimeric antigen receptor T cell therapy, are developed and more cell surface antigens that is highly specific for GBM cells are needed. Although extensive transcriptome analyses or proteomic analysis of GBM cells were performed, few transcripts specific for GBM cells have been identified. However, GBM cell-specific antigen epitopes formed by post-translational modifications of proteins may have been missed by transcriptome or proteomic analysis, and could still be discovered by thoroughly searching for cancer-specific monoclonal antibodies. In this study, we aimed to identify GBM-specific antigens using a monoclonal antibody library from patient-derived tumor spheres, create CAR-T cells against the antigen, and check antitumor efficiency of the CAR-T cells. Approximately 25,000 monoclonal antibody-producing hybridomas were establishment using BALB/c mice and patient derived tumor spheres. Among them, a antibodies that bind to plural glioblastomas and not to plural normal brain cells were selected and we identified the antigen as Prostaglandin F2 receptor negative regulator (PTGFRN) by the expression cloning method. PTGFRN witch is expressed in several cancers regulate migration, angiogenesis, and cell polarity and decreases the radiosensitivity of GBM cells. We created CAR-T cells against the antigen and co-cultured it with GBM cells, which significantly increased the production of IL-2 and INF-γ. Furthermore, the CAR-T cells injected intracranial in an orthotopic xenograft model with patient-derived GBM cells, significantly reduced tumor growth. PTGFRN CAR-T-cell therapy may be a potential novel therapeutic target for GBM.
TMIC-64. EXPLORING ULTRASTRUCTURAL PATHOLOGY IN GLIOMAS: INSIGHTS FROM RECENT STUDIES
Authors: Muhammad Sulman, Orwa Aboud
Journal: Neuro-Oncology (2024)

Abstract Glioma tumors arise from the glial cells making up to 40% of the brain tumors, and contributing up to 85% of the malignant tumors of the brain. Gliomas are a heterogeneous group of tumors classified based on various factors such as genetics, molecular profiles, etc. Glioblastoma, an aggressive form of gliomas, has incredibly low survival of only 15 months suggesting that thorough research, improved diagnostics, and therapeutics development is needed to improve the outcomes for patients with gliomas. These advancements require a critical analysis of the microenvironment of gliomas to understand the pathophysiology at play. Ultrastructural analysis (UA) using high-resolution electron microscopy offers crucial insights into the cellular and subcellular characteristics of gliomas, revealing organelle abnormalities and confirming molecular alterations. In this review, we focus on the recent developments exploring the ultrastructural pathology of gliomas. UA shows a detailed microenvironment of gliomas to reveal the abnormal presence of lipids in the intra- and extracellular environment of gliomas accompanied by the disrupted structure of the cellular membranes and organelles. The disruptions were noted in the blood vessels of the tumors displaying intriguing details regarding the formation of neovasculature and the absence of typical contents of vessel walls like endothelial cells. A comparative survey of the mitochondrial ultrastructure of gliomas with or without IDH1 mutations also reveals the role of UA in deciphering the impact of different mutations on the microenvironment level. Here, we also discuss the major implications of these findings regarding the research direction, diagnostic modalities, and therapeutic options.