tbuckley/cabot-search huggingface dataset:
CSIG-15. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS VIA THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION
Authors: Pin-Yuan Chen, Pei-Yu Liu, Chiungyin Huang, Hsiang-Tsui Wang
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.
CSIG-17. ADHESION GPCR BAI1/ADGRB1 CAN BLOCK IGF1R-MEDIATED GROWTH SIGNALLING, INCREASE RADIOSENSITIVITY AND AUGMENT SURVIVAL IN MEDULLOBLASTOMA
Authors: Takahiro Yamamoto, Virginea Araujo De Farias, Yuki Kuranaga, Dan Zhu, Rashed R Parag, Satoru Osuka, Erwin G Van Meir
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is an aggressive pediatric brain tumors and increased knowledge about the disease mechanisms is needed to develop new therapeutic approaches. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is an adhesion GPCR receptor and tumor suppressor epigenetically silenced in MB. Our prior studies showed that BAI1 can bind the MDM2 E3 ubiquitin ligase and relocate it to the cell membrane, thereby preventing it from degrading p53 in the nucleus (Zhu et al, Cancer Cell, 2018). Whether other MDM2 targets are affected by this relocation that may be functionally important in MB development is unknown. We hypothesized that BAI1-mediated relocation of MDM2 might destabilize cell surface oncogenic receptors and found that BAI1 stimulates IGF1R poly-ubiquitination and degradation. Mechanistically, BAI1 fosters MDM2-IGF1R interaction through beta-arrestins, adaptor proteins connecting MDM2 to IGF1R. Epigenetic reactivation of BAI1 expression suppressed Stat3 and Akt signaling, and radio-sensitized MB cells, leading to significantly improved survival in orthotopic MB xenograft models in mice regardless of tumor p53 mutation status. These findings are important as they demonstrate that BAI1 has dual anti-tumor effects in MB through MDM2 membrane re-localization, stabilizing p53 and blocking IGF1R signaling. They further suggest that epigenetic targeting of BAI1 is a promising therapeutic approach for clinical translation.
CTIM-21. FIRST-IN-HUMAN PHASE I CLINICAL TRIAL USING 8R-70CAR T CELLS FOR NEWLY DIAGNOSED ADULT GLIOBLASTOMA
Authors: Ashley Ghiaseddin, Haipeng Tao, Phuong Deleyrolle, Maryam Rahman, Serendipity Zapanta Rinonos, Jesse Kresak, Tara Massini, John Hiemenz, Christopher robinson, Jack Hsu, Tuo Lin, Kristine Wynne, Jennifer King, Marcia Hodik, John Lybarger, Eugenio Simon Manso, Anqi Wang, David Sekora, Kathryn McKibben, Anjelika Dechkovskaia, Paul Castillo, John Ligon, Elias Sayour, Loic Deleyrolle, Duane Mitchell, Jianping Huang
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To address the challenges of chimeric antigen receptor (CAR) T cell therapy in GBM, we utilized IL-8 release from tumor cells as a ‘GPS homing signal’ to enhance T-cell trafficking with a novel CD70-specific CAR design (8R-70CAR) that targets GBM. The 8R-70CAR offers several advantages: 1) Improved CAR T-cell trafficking, enhancing antitumor efficacy; 2) Reduced CD70, reshaping the tumor microenvironment (TME) and boosting endogenous immunity; 3) Utilized CD27 as the CAR, a co-stimulatory molecule that enhances T-cell functions; 4) Enabled CAR T cells to act as a sink to neutralize or remove IL-8, a pro-cancer chemokine, from the TME; and 5) Required only 120 ml of whole blood (not leukapheresis) for CAR T cell production. Preclinically, 8R-70CAR significantly enhanced CAR-T cell tumor migration and persistence, leading to complete tumor regression and sustained immune memory in a chemo/radiation/PD-1-blockade-resistant GBM model. These findings led to a phase-I trial (IMPACT trial: FDA-IND#23881, NCT05353530) using 8R-70CAR T cells for CD70 -positive newly diagnosed adult GBM. METHODS We aim to recruit 18 adult patients (3 + 3 dose-escalation design) with CD70-positive (&amp;gt;20%) tumors. The CAR T cells will be given intravenously after completing standard-of-care (SOC) therapy. Primary endpoints: Evaluate safety, tolerability, and dose-limiting toxicities (DLTs) to determine the maximum tolerated dose. Secondary endpoints: Assess preliminary efficacy. Immune monitoring and correlative studies will also be conducted. RESULTS To date, four patients have been enrolled in the IMPACT trial, with 2 eligible patients participating in treatment at dose level 1 (1x10^6/kg). One patient has completed treatment with 8R-70CAR T cells, experienced no DLTs, and is currently in follow-up. The remaining patient is under SOC therapy before receiving CAR T cell treatment. CONCLUSIONS This study aims to address current therapeutic gaps and offers options for implementing a novel CAR design for the development of a more effective therapeutic modality for GBM.
TMIC-86. THE ROLE AND THERAPEUTIC RESEARCH OF NETS IN PROMOTING TMZ RESISTANCE IN GLIOBLASTOMA
Authors: Shiguang Zhao
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE This study aims to investigate the issue of resistance to temozolomide (TMZ) treatment in high-grade glioblastoma (GBM), specifically the association between TMZ resistance, the tumor microenvironment (TME), and neutrophil activity. The research hypothesis posits that changes in neutrophils induced by TMZ treatment, particularly the formation of neutrophil extracellular traps (NETs), may lead to TMZ resistance in GBM cells. METHODS The study utilized clinical data analysis and animal model research to evaluate changes in neutrophils during TMZ treatment and their impact on treatment efficacy. Proteomics analysis and high-throughput sequencing were employed to investigate the effect of TMZ on cytokine secretion by GBM cells and how these cytokines stimulate the release of NETs. Additionally, gene ontology (GO) analysis and bioinformatics methods were used to study how NETs promote the epithelial-mesenchymal transition (EMT) process and TMZ resistance by activating specific signaling pathways such as Jak-Stat3. RESULTS The study found that TMZ treatment led to increased neutrophil infiltration, which was associated with poor prognosis in GBM patients. TMZ treatment altered the levels of cytokines secreted by GBM cells, particularly IL-6, promoting the release of NETs by neutrophils. The formation of NETs was closely related to the activation of Stat3 signaling and the promotion of the EMT process in tumor cells, thereby enhancing TMZ resistance. Magnesium-based micromotors were found to improve TMZ efficacy by scavenging ROS production in neutrophils, inhibiting the release of NETs. CONCLUSION This study confirms the association between TMZ resistance and neutrophil activity, particularly the role of NETs in promoting EMT and resistance. These findings provide new insights into the treatment of GBM and offer a theoretical basis for the development of therapeutic strategies targeting NETs, which may improve the response of glioblastoma to TMZ treatment by inhibiting ROS production. The development of this novel therapeutic approach offers new treatment options for postoperative chemotherapy in GBM.
EPID-19. INTERACTION BETWEEN GERMLINE AND SOMATIC GENETICS TO ELUCIDATE RISK OF ADULT DIFFUSE GLIOMA
Authors: Jeanette Eckel-Passow, Matthew Kosel, Paul Decker, Thomas Kollmeyer, Kristen Drucker, Annette Molinaro, Stephen Francis, John Wiencke, Margaret Wrensch, Daniel Lachance, W Oliver Tobin, Robert Jenkins
Journal: Neuro-Oncology (2024)

Abstract Acquired tumor alterations are part of the WHO diagnosis of glioma. However, germline predisposition to these alterations is unknown. GWAS in European and Asian populations identified germline variants in 30 regions, many in or near genes that also acquire alterations, suggesting that interactions between inherited and acquired genetics are involved in glioma development. To evaluate such interactions, we used 3686 glioma cases and 1889 controls. A case-control design and multinomial logistic regression were used to identify germline variants associated with development of TERT-promoter mutant gliomas, generating two interesting observations. First, TERT germline variants were associated with predisposition to IDHwt glioma that have a TERT promoter mutation, but not with IDH-mutant codeleted gliomas that have a TERT promoter mutation. Second, two novel regions were observed in this more homogeneous subgroup of TERT mutated tumors: variants in TXNDC11 (OR=2.66, p=5.7x10-8) and RUVBL2 (OR=3.1, p=5.8x10-8). High tumor expression of TXNDC11 is associated with poor prognosis in glioma and RUVBL2 interacts with TERT to affect telomerase activity. Similar analyses are being performed on additional clinically relevant acquired alterations. In parallel, case-case GWAS analyses were performed to evaluate germline variants associated with other tumor alterations. Comparing IDH-mutant versus IDHwt stratified by rs55705857 genotype, the most significant variants were PHLDB1 (p=1.2x10-13) and D2HGDH (p=2.1x10-10), highlighting the importance of these two variants independent of CCDC26 for the development of IDH-mutant glioma. As a parallel approach, we utilized recursive partitioning and regression trees (rpart) to classify IDH mutation status using the 30 known variants. The top four branches of the regression tree included CCDC26, D2HGDH, PHLDB1, and MAML2, as well as two Asian variants (RAB27A, CYP4F12). This highlights the importance of utilizing variants discovered in non-European populations in analyses. Overall, understanding these interactions are necessary to develop therapeutics, stratify clinical trials, and to develop relevant tumor models.
CTIM-11. LONG-TERM SURVIVORS FROM A PHASE 1B STUDY OF IGV-001 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Raul Perez-Olle, Greg K Pennock, Charles Scott, Carrie Andrews, Jenny Zilberberg, D Craig Hooper, Kevin D Judy, Mark A Exley, David W Andrews
Journal: Neuro-Oncology (2024)

Abstract Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed glioblastoma (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers (BDCs) implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM (Andrews et al., 2021), including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. The Phase 1b study enrolled 33 patients in four different cohorts implanted with 10 or 20 BDCs for 24 or 48 hours. Here we report on 6 subjects with survival beyond 4 years, including 5 subjects who survived 5 years or more (15.2%). There were 4 male and 2 female subjects, with a median age of 52 years (range 32-75). At diagnosis the MGMT promoter was methylated in 4 of 5 subjects that survived 5 years or more. We also report on T cell receptor Vβ CDR3 region sequencing of peripheral blood mononuclear cells and tissue infiltrated lymphocytes that was performed in a subset of 9 patients, including 3 subjects who survived beyond 4 years. Immune correlates of IGV-001 suggest an association between peripheral T cell clonal expansion and PFS/OS outcomes. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949) has completed enrollment and results are expected to be available in 2025.
EPID-18. PATTERNS OF CARE AND CLINICAL OUTCOMES OF PATIENTS WITH GLIOBLASTOMA FROM 2005-2020: A REAL-WORLD ANALYSIS
Authors: Diya Jayram, Shreyas Bellur, Ahmad Ozair, Shahzaib Ahmad, Lydia Hodgson, Numa Frias, Vivek Podder, Mohammad Arfat Ganiyani, Manmeet Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Survival for glioblastoma (GBM) remains low, with disparities affecting outcomes. Standard of care (SoC) includes surgery and adjuvant chemoradiation. This study explores demographics, treatment patterns, and outcomes of GBM patients in the United States. METHODS A retrospective study was conducted on patients with GBM in the National Cancer Database for GBM patients between 2005-2020 according to ESMO Guidance for Reporting Oncology Real-World (GROW). Trends were analyzed with descriptive statistics and X2-test between time periods: 2005-08, 2009-12, 2013-16, and 2017-20. Predictors of SoC receipt were analyzed with multivariate logistic regression. Median overall survival (mOS) estimated using Kaplan-Meier and Cox regression models. Adjustment made using demographic, socioeconomic, and clinical factors. Outcomes reported as (Odds Ratio [OR]/Hazard Ratio [HR] 95% Confidence Interval) per STROBE guidelines. RESULTS Of 104,697 GBM patients, 42.5% were female. 91.2% White, 5.7% Black, and 2.0% were Asian. 5.3% were Hispanic. Median age was 65 years (IQR:57-73). Percentage of patients ≥65 years increased from 48.8% in 2005-08 to 54.0% in 2017-20. 56.5% of patients received SoC. SoC usage increased over time: 2009-12 (OR:1.26, 1.21-1.31, P&amp;lt;0.001) vs 2013-16 (OR:1.36, 1.31-1.41, P&amp;lt;0.001) vs 2017-20 (OR:1.51, 1.45-1.57 P&amp;lt;0.001). Females (OR:0.91, 0.89-0.93 P&amp;lt;0.001), Black (OR:0.81, 0.77-0.86 P&amp;lt;0.001), and Hispanics (OR:0.92, 0.86-0.97, P=0.004) were less likely to receive SoC than males, White, and non-Hispanics. Privately insured were more likely to receive SoC than Medicare (OR:0.83, 0.80-0.87, P&amp;lt;0.001), Medicaid (OR:0.68, 0.64-0.71, P&amp;lt;0.001), and uninsured patients (OR:0.60, 0.55-0.64, P&amp;lt;0.001). SoC recipients had mOS of 14.6 months (14.5-14.8) vs 4.8 (4.7-4.9) for non-recipients (P&amp;lt;0.001). Compared to 2005-08, survival improved over time: 2017-20 (HR:0.83, 0.82-0.85, P&amp;lt;0.001) vs 2013-16 (HR:0.88, 0.86-0.89, P&amp;lt;0.001) vs 2009-12 (HR:0.93, 0.91-0.94, P&amp;lt;0.001). CONCLUSIONS Receipt of SoC has risen with significant increase in survival. However, female, Black, and Hispanic patients were less likely to receive SoC. Targeted efforts are warranted to mitigate disparities.
EPID-14. PATTERNS OF CARE AND PROGNOSTIC FACTORS FOR PATIENTS WITH BRAIN METASTASES FROM COLON CANCER: A REAL-WORLD STUDY
Authors: Diya Jayram, Lydia Hodgson, Shreyas Bellur, Shahzaib Ahmad, Samuel Sommer, Ahmad Ozair, Numa Frias, Manmeet Ahluwalia
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BMs) from colon cancer (CC) have limited published literature. This work sought to examine patterns of care and prognostic factors for patients with CC BMs. METHODS A retrospective study was conducted on patients with CC BMs in the National Cancer Database between 2010-2020 and reported using STROBE guidelines. Treatment was stratified into receipt of stereotactic radiosurgery only (SRS), whole brain radiation only (WBRT), systemic therapy only (Sys), combination therapy, and no brain-directed treatment (NoTx). Median overall survival (mOS) and prognostic factors were determined using multivariate cox proportional hazards adjusting for age, sex, race/ethnicity, insurance, Charlson-Deyo score (CDS), concurrent metastases (CMs), and treatment. Outcomes were reported as hazard ratio (HR) and 95% confidence intervals. RESULTS Among 1,383 BMs patients, median age was 64.0 years (IQR 56.0-73.0). 46.4% were female and 81.2% were White. Overall mOS (95% CI) was 5.6 months (4.5-6.2). 26.1% had bone, 71.5% had lung and 72.4% had liver CMs. 24.4% underwent WBRT+Sys, 22.6% NoTx, 18.5% Sys, 14.8% SRS+Sys, 14.7% WBRT, and 5.0% SRS. Patients who underwent SRS+Sys had the highest mOS of 14.4 months (12.8-16.3) followed by Sys: 11.6 months (8.6-13.4), WBRT+Sys: 9.5 months (8.5-10.9), SRS: 3.2 months (2.5-4.4), WBRT: 2.5 months (2.2-2.8), and NoTx: 2.5 months (2.2-2.8) (P&amp;lt;0.001). Patients treated with WBRT+Sys (HR:1.2, 1.0-1.5, P=0.028), SRS alone (HR:1.8, 1.4-2.5, P&amp;lt;0.001), WBRT alone (HR:3.6, 2.9-4.4, P&amp;lt;0.001), NoTx (HR:2.5, 2.0-3.0, P&amp;lt;0.001) was associated with significantly lower survival than SRS+Sys. Patients treated at non-academic facilities (HR:1.1, 1.0-1.3, P=0.038), with Medicare-insurance (HR:1.2, 1.1-1.5, P=0.013) and with left-sided mCC (HR:0.8, 0.7-0.9, P&amp;lt;0.001) had lower survival. CONCLUSIONS SRS+Sys was associated with the highest survival in patients with CC BMs, however only 14.8% received it. Notably, 22.6% of patients received NoTx. Further prospective studies exploring factors behind heterogeneity in clinical care are warranted.
CTIM-27. DOC1021 CELL-BASED VACCINATION AS ADJUVANT THERAPY FOR GLIOBLASTOMA: PHASE I CLINICAL TRIAL ANALYSIS
Authors: Yoshua Esquenazi, Jay Zhu, Sigmund Hsu, Rodrick Zvavanjanja, Mia Vu, Eva Highberg, Trivedi Akshar, Wei Liu, Madhuri Namekar, Colby Hofferek, James Ernste, Corey Mossop, Clay Christina, Sabina Amin, Musher Benjamin, Vinod Ravi, Kemnade Jan, Laura Aguilar, Alan Turtz, Nitin Tandon, Vanaja Konduri, Joseph Georges, William Decker
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is an aggressive tumor for which median survival remains 14-18 months despite aggressive standard of care. Cellular immunotherapy approaches have recently shown promise. Homologous antigenic loading is an ex-vivo technique that leverages p38MAPK and mTORC1 signaling cascades to initiate powerful cDC1-like skewing in monocyte-derived dendritic cells, leading to downstream induction of tissue-infiltrating, cytolytic effector memory T-cells. This open-label phase I clinical trial evaluated the autologous dendritic cell vaccine DOC1021 prepared through homologous antigenic loading and administered bilaterally near the deep cervical lymph nodes. Three courses of vaccine were administered every 2 weeks after completion of chemoradiation, adjuvanted concurrently with six weeks of weekly type I interferon. Four dose levels from 3.5x106 to 3.6x107 total vaccine cells were tested. Tumor progression prior to vaccination was not an exclusion criterion. Sixteen newly diagnosed IDH-WT patients completed treatment, median age 63 years and 94% MGMTp unmethylated. The most common related AEs were grade 1 injection-site reactions and grade 1-3 fatigue and urticaria. No DLTs were observed. Immunohistochemistry of tumors derived from early post-vaccination second resections showed enhanced CD8+ T-cell infiltration and pathologic findings consistent with residual rather than relapsed GBM in 2/3 patients. Analysis of post-vaccination PBMC in dose level cohorts 2-4 indicated expansion of both CD4+ (13/13) and CD8+ (11/13) central memory T-cell compartments (p&amp;lt;0.002 and p&amp;lt;0.05, respectively) as well as expansion of CD8+CD127+ T-cells (12/13; p&amp;lt;0.001). Among three patients for whom tissue was obtained pre- and post-vaccination, clinical outcomes correlated with Visium spatial transcriptomic analysis. Median survival for the MGMTp unmethylated cohort (n=15) has not yet been reached but is statistically greater (p&amp;lt;0.05) than that of matched historic controls. The results indicate that DOC1021 is safe, can be effectively integrated within existing standards of care and is potentially efficacious in a challenging patient population.
QLTI-22. TEMOZOLOMIDE CHEMOTHERAPY EFFECTS ON GLIOMA PATIENT FERTILITY AND THEIR OFFSPRING: A RETROSPECTIVE REVIEW
Authors: Austin Lu, Mia Vu, Eva Schuman, Cornelius Ware, Sigmund Hsu, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2024)

Abstract Gliomas represent ~30% of primary brain tumors. Temozolomide (TMZ) chemotherapy with concurrent radiation or following radiation is the main course of treatment. Avoidance of pregnancy in female patients and partner of male patients is strongly encouraged due to unknown teratogenic and long-term effects to the health and development of fetus. Patients of childbearing age must wrestle with receiving TMZ treatment, potentially impacting fertility, and the desire for biological children in the future. Gamete preservation prior to TMZ induction is the current solution, which is often financially prohibitive, leaving patients to consider natural conception after completion of TMZ. We intend to identify potential difficulties in conception, pregnancy complications, birth abnormalities, and childhood developmental deficiencies that may be correlated to TMZ exposure prior to conception. Included patients conceived and delivered one or two children after completing treatment with TMZ. All patients received antiepileptic drugs (range = 1-4) which have variable known teratogenic effects during pregnancy. We identified 13 patients (7 male, 6 female; median age of 29) with diagnoses of astrocytoma (n=5), oligodendroglioma (n=5), oligoastrocytoma (n=2; diagnosed prior to 2021 WHO classification), and glioblastoma (n=1). Two reported issues with conceiving (1 male and 1 female) and 17 children were born. One child had developmental abnormalities (6%), and all other 16 children were healthy per parental assessment. Complete results of pregnancy complication and childhood development data will be updated at the meeting. Information on teratogenic and developmental effects of TMZ in humans is largely unknown. Animal studies have shown an increase in fetal malformations when exposed to TMZ during pregnancy. Despite the limitations of a retrospective study, our findings suggest that natural conception after the conclusion of TMZ treatment may be safer than suspected. Given the limited sample size, future comprehensive studies are warranted to corroborate these observations.