tbuckley/cabot-search huggingface dataset:
CTIM-19. A PHASE 1, SAFETY LEAD-IN AND RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH-1 MUTANT GLIOMA: TRIAL IN PROGRESS
Authors: Patrick Wen, Macarena de la Fuente, Priya Kumthekar, Katherine Peters, Jennifer Clarke, John de Groot, Isabel Arrillaga-Romany, Vinay Puduvalli, Ingo Mellinghoff, Robert Chong, Payal Jain, Valentine Barboux, Michael Chisamore, Michelle Abshire, Paria Mahboub-Johnson, Islam Hassan, Jeffrey Knipstein, Timothy Cloughesy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of isocitrate dehydrogenase 1/2 mutant (mIDH1/2) enzymes. VOR is being investigated in a phase 3 study in residual or recurrent grade 2 non-enhancing gliomas, in which interim analysis showed VOR significantly improved progression-free survival and delayed time to next intervention. A prior neoadjuvant perioperative study in recurrent, non-enhancing grade 2/3 gliomas showed that VOR treatment was associated with interferon signal activation and increased T-cell infiltration, suggesting 2-hydroxyglutarate suppression may prime the tumor immune microenvironment for immune checkpoint blockade. This study (NCT05484622) evaluates the safety and tolerability of VOR+pembrolizumab to determine the recommended combination dose (RCD) of VOR (safety lead-in phase) and evaluates CD3+ T-cell infiltration in tumors following a 28-day preoperative period. METHODS Enrollment: US patients with recurrent or progressive grade 2/3 mIDH1 R132H glioma. Key eligibility: measurable enhancing disease, Karnofsky Performance Status ≥70, resectable (perioperative phase only). Following a March 2024 protocol amendment, inclusion criteria were expanded to include patients with oligodendroglioma in addition to patients with astrocytoma. Safety lead-in dosing: Cohort 1, VOR 40mg QD+pembrolizumab 200mg Q3W in 21-day cycles. The perioperative phase is randomized 1:1:1 to preoperative combination, VOR 40mg QD, or untreated for 28 (+7) days; all patients could opt to receive the VOR RCD in combination with pembrolizumab 200mg Q3W postoperatively. Primary objectives: safety and tolerability of VOR RCD administered with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with combination compared to untreated tumors. RESULTS Seven patients with recurrent or progressive enhancing grade 2/3 astrocytoma with an mIDH1 R132H were dosed in the safety lead-in phase. No dose-limiting toxicities were detected during this phase. CONCLUSION VOR 40mg QD+pembrolizumab 200mg Q3W was confirmed as the RCD for the perioperative phase. This phase was opened to enrollment in May 2023, and recruitment is ongoing.
TMET-13. SPATIAL METABOLOMIC CHANGES OF NUCLEOTIDE IN THE BRAINS OF ORTHOTOPIC MOUSE GLIOMA MODEL AFTER BORON NEUTRON CAPTURE THERAPY (BNCT)
Authors: Natsuko Kondo, Nao Kobayashi, Yoshinori Sakurai, MInoru Suzuki, Shinichi Yamaguchi, Masaya Ikegawa
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is the most lethal primary brain tumor. Boron Neutron Capture Therapy (BNCT) is a tumor-selective particle radiation therapy, in which high-LET α-particles and recoil 7Li are produced by the capture reaction between 10B and thermal neutrons and it has extended the prognosis of glioblastomas [Kawabata S, et al., Neuro-Oncology Advances 3(1), 1–9, 2021]. Augmented synthesis and use of nucleotide triphosphates is critical and universal metabolic dependency of tumor cells [Mullen, N.J., Singh, P.K. Nat Rev Cancer 23, 275–294 (2023)]. However, the effects of BNCT on metabolism of purine and pyrimidine in brain tumors and the surrounding normal brain are unknown. We spatially investigated metabolomic change in brains of orthotopic mouse glioma model, before and 2, 7, and 14 days after BNCT using mass spectrometry imaging (MSI). By separating tumor and non-tumor areas and performing Partial Least Squares Regression calculations, we have successfully visualized tumor-specific metabolites including adenine (ATP, ADP) and uridine (UTP, UDP-glucose, UDP-GlcNAc) with MSI. Of note, the signal of top-scored tumor specific metabolite, UDP-GlcNAc dramatically decreased and disappeared as the tumor regressed. Furthermore, the signal of ADP which was supposed to be released from tumor, colocalized with invading tumors along with corpus callosum. The value of adenylate energy charge, ([ATP]+0.5[ADP]/[ATP]+[ADP]+[AMP]) in the surrounding normal brain of the untreated tumor-bearing mouse increased up to 0.37 and decreased gradually down to 0.32 with BNCT, approaching to the value of normal control mouse brain, 0.27. These metabolomic changes reflected the tumor-killing effect and restoration of energy charge of surrounding normal brain by BNCT and have potential significance for development of biomarker or diagnosis.
IMMU-50. IMPACT OF SARS-COV-2 MRNA VACCINES ON PD-L1 EXPRESSION IN INTRACRANIAL TUMORS
Authors: Adam J Grippin, Sage Copling, Andrew Kim, Rishabh Lohray, Wen Jiang, Yon Son Betty Kim, Steven H Lin
Journal: Neuro-Oncology (2024)

Abstract Although immune checkpoint inhibitor (ICI) effectiveness is correlated with intra-tumoral PD-L1 expression, there are no clinically available methods to improve sensitivity to ICIs by modulating PD-L1 expression. mRNA vaccines stimulate robust interferon-dependent innate immune activation leading to four-fold increases in PD-L1 expression on peripheral and intratumoral myeloid cells and enhanced sensitivity to immune checkpoint blockade in preclinical models (Sayour, Grippin, et al., NanoLetters, 2018; Mendez-Gomez, et al., Cell, 2024). We hypothesized that mRNA vaccines targeting SARS-COV-2 would similarly enhance PD-L1 expression in intracranial tumors. To test this hypothesis, we utilized institutional databases to identify 5,524 patients at our institution with pathology reports including the term “PD-L1” from August 2020 to November 2023. Pathological data and dates of SARS-COV-2 vaccination were compiled for each patient. Across the entire cohort (n=5,524), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a 55% increase in mean tumor proportion score (TPS) (14% vs 8.9%, p=0.029). In the subset of patients with intracranial tumors (n=187), receipt of a SARS-COV-2 mRNA vaccine within 100 days of biopsy was associated with a massive increase in TPS (57% vs 7.2%, p&amp;lt;0.001). To evaluate the impact of this change on clinical outcomes with immunotherapy, we utilized a second institutional database to assemble a cohort of patients with Stage IV melanoma with intracranial metastasis treated with immune checkpoint blockade during the period August 2020 through November 2023. Patients who received a SARS-COV-2 vaccine within 100 days of initiation of ICI (n=10) exhibited numerically improved overall survival compared to those without SARS-COV-2 mRNA vaccine (n=38) (HR 0.50, 95% CI 0.22-1.2, p=0.06). Median overall survival was 545 days among patients without COVID mRNA vaccination and was not met among those with COVID mRNA vaccination. This data supports further investigation of the immune modulating effect of SARS-COV-2 mRNA vaccines in patients with intracranial tumors treated with immune checkpoint blockade.
QLTI-03. REAL-WORLD PARADIGM FOR TREATMENT OF PRIMARY CNS LYMPHOMA PATIENTS IN CLINICAL PRACTICE
Authors: Yoshie Umemura, Lakshmi Nayak, Marcel Nijland, Nimish Mohile, Tracy Batchelor, Roy Strowd
Journal: Neuro-Oncology (2024)

Abstract Although high-dose methotrexate (HD-MTX) is the foundation of induction therapy for primary CNS lymphoma (PCNSL), a gold-standard regimen has yet to be established. A 10-case-based survey, to assess the practice patterns at key decision-points in adult PCNSL management outside of clinical trials, was distributed through IPCG, HOVON, and AAN Neuro-Oncology Section. Eighty-five responses were collected from North American (N=42), European (N=33), Asian (N=7), and other countries (N=3) from neurologist neurooncologists (N=35), hem-onc neurooncologists (N=24), hematologist-oncologists (N=18), neurosurgeons (N=5), radiation-oncologist (N=2), and hematopathologist (N=1). The most common first-line induction regimen was R-MP+/-V: rituximab, HD-MTX, procarbazine, +/-vincristine (N=28) followed by MATRix: HD-MTX, cytarabine, thiotepa, rituximab (N=23), then R-MT: rituximab, HD-MTX, temozolomide (N=19). For elderly patients, R-MP+/-V remained most common (N=32). The majority preferred to omit intra-CSF chemotherapy (N=50). The most preferred consolidation after complete response was high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT, N=57), or high-dose cytarabine (N=17) in elderly patients. In cases of partial response, the most common approach was still HDC-ASCT (N=24). For stable disease, participants would move to various salvage chemotherapy (N=33), continue additional induction (N=39), or to move to radiotherapy (N=10). If early progression was noted, the most preferred approach was non-methotrexate chemotherapy (N=31). For recurrences after previous complete response and HDC-ASCT consolidation, the majority preferred to try chemotherapy before moving to radiotherapy in scenarios &amp;lt; 1 year (N=64) or &amp;gt; 1 year from consolidation (N=68), and even if the performance status was poor (N=57). Close to half (N=34) participants felt there is a role for stereotactic radiosurgery in various clinical settings. This survey noted clear consensus to use multi-drug MD-MTX based chemotherapy, and common induction regimens, however, highlighted a great variety of treatment preferences after first-line therapy even amongst disease experts through clinical consortiums, suggesting likely wider range of treatments and disease response in larger community settings.
QLTI-05. EUROPEAN NEURO-ONCOLOGY QUALITY ASSURANCE (ENOQUA): AN EORTC BRAIN TUMOR GROUP STUDY
Authors: Evangelia Razis, Peter Hau, Thierry Gorlia, Nicolaus Andratschke, Brigitta Baumert, Philipp Lohmann, Anastasia Vernadou, Jens Gempt, Filip De Vos
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Neuro-Oncology, a complex and multidisciplinary field that is relatively recent, lacks well-established quality assurance measures and standards for patient care. METHODS We assessed the performance of 14 potential quality indicators across 19 EORTC Neuro-Oncology centers to validate these indicators as effective measures of quality. For each center, we abstracted records from 20 patients diagnosed with glioblastoma in 2018 who were not enrolled in an investigational study. We tested associations between patient survival, center characteristics, and the performance of these quality measures. RESULTS Most centers met several standard requirements, suggesting their potential acceptance for prospective validation. IDH expression data was universally recorded in the patients’ chart. Performing MRI within 72 hours of surgery and providing patient education for chemotherapy correlated with improved overall survival (OS). Standards met in the majority of centers were the presence of a multidisciplinary plan, a radiation plan and the extent of surgery recorded in the chart, as well as the referral for radiation within six weeks of diagnosis. Preliminary results indicate that academic centers outperformed others in most measures, although analysis is ongoing. Performance varied significantly across centers; some standards were consistently met poorly, highlighting areas needing improvement. Lack of universal acceptance of certain practices as necessary and/or important may render some standards inappropriate for further development. Final analysis will be presented at the meeting. CONCLUSION We are developing a comprehensive set of standards and measures for QA in neuro-oncology, which will require future prospective validation.
IMMU-16. ANTI-VEGF TREATMENT EFFECT AGAINST GLIOMA IS IMMUNE DEPENDENT AND MEDIATED BY ENHANCED T CELL ACTIVITY
Authors: Cecile Maire, Malte Mohme, Krystian Fita, Merle Reetz, Sarina Heinemann, Eva Tolosa, Malik Alawi, Christian Casar, Michael Spohn, Jens Gempt, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2024)

Abstract Immunotherapy trials in glioblastoma patients increasingly avoid immunosuppressive steroids and consider bevacizumab as alternative anti-edema treatment. Since VEGF is also a potent immunosuppressive factor, we explored the dimension and mechanisms of immune-mediated effects of anti-VEGF treatment. Murine glioma cells were injected intracerebrally into C57BL/6 wild-type mice or immunodeficient Pfp/Rag2 knockout mice and animals were treated with B20 (anti-murine VEGF) or dexamethasone. Immune cells were profiled by flow cytometry, and RNAseq was performed on sorted tumor and immune cells at different timepoints. B20 prolonged the survival of immunocompetent mice but not of Pfp/Rag2 knockout mice, indicating that the immune system is essential for its effect. At an early timepoint when controls became symptomatic, B20 “early” tumors (B20-ea) showed increased infiltration with T cells and myeloid cells, and decreased vascularization, whereas B20 tumors at the survival endpoint resembled IgG-controls. Gene expression in B20-ea tumor cells was dominated by hypoxia, neural development, invasion, TGF-β, Notch and Wnt signatures as well as concerted upregulation of Kmt2 H3K4 methyltransferases. In CD11b+ myeloid cells from B20-ea tumors, M1 hallmark genes and T cell activation genes were upregulated, while M2 genes were downregulated. Deconvolution revealed a transient shift towards pro-immune microglia/macrophages as well as increased NK cells and DCs. In CD8+ and CD4+ T cells, B20 increased the expression of S1pr1 and α/β TCR genes. The proportion of progenitor-like exhausted CD8+ cells, which are responsive to PD-1 blockade, was increased in B20-ea. In CD4+ cells, B20 caused skewing towards TFH, while dexamethasone increased TH2 cytokine expression. Depletion experiments demonstrated that CD8+ and CD4+ T cells but not NK cells were necessary for the survival-prolonging effect of B20. To conclude, anti-VEGF therapy has significant immunostimulatory effects which are, however, largely transient, so that an early treatment window of opportunity may exist during which it could actively support immunotherapy.
NIMG-41. MULTI-SITE, PROSPECTIVE TRIAL EVALUATING FET-PET IN GLIOBLASTOMA (FIG) STUDY (TROG 18.06): PRELIMINARY RESULTS OF CENTRAL NUCLEAR MEDICINE REVIEW OF FET-PET BIOLOGIC TARGET VOLUME DELINEATION FOR RADIATION PLANNING
Authors: Eng-Siew Koh, Roslyn Francis, SzeTing Lee, Eddie Lau, Elizabeth Thomas, Angela Whitehead, Olivia Cook, Rachael Dykyj, Alisha Moore, Alana Rossi, Paul Thomas, David Pattison, Tim Akhurst, Ramin Alipour, Edward Hsiao, Geoffrey Schembri, Peter Lin, June Yap, Tam Ly, Ian Kirkwood, Wilson Vallat, Dayanethee Krishna Krishna, Shahroz Khan Khan, Stanley Ngai Ngai, Chris Yu, Scott Beuzeville, Tow Chan Yeow, Nathaniel Barry, Martin Ebert, Hui Gan, Bradford Moffat, Greg Fitt, Sweet Ping Ng, Mark Pinkham, Dale Bailey, Andrew M Scott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To provide an update from the multi-site trial evaluating O-(2-[18F]-fluoroethyl)-L-tyrosine Positron Emission Tomography (FET-PET) in Glioblastoma (FIG) study and 2) assess the impact of central Nuclear Medicine physician (NMP) review of prospective FET-PET1 delineation of the biological target volume (BTV) for radiotherapy (RT) planning. Material and methods Up to 210 adult GBM participants across 11 Australian sites will undergo FET-PET post-surgery/pre-chemo-RT [CRT] (FET-PET1), one month post CRT (FET-PET2) and at suspected progression (FET-PET3). Group 1 participants enter at timepoint 1 (FET-PET1 with MRI1), with Group 2 entering at timepoint 2. Adjuvant RT target volumes are derived per standard contrast MRI with hybrid post-hoc RT volumes then incorporating the FET-PET1 NM-derived BTV utilising MiM version 7.0. All trial sites and NMP have passed credentialling which included three benchmarking cases involving BTV delineation. RESULTS Trial recruitment commenced in January 2021, with 189 (n=126 Group 1 and n=63 Group 2) participants enrolled to date, with a target of 140 Group 1 participants. During trial credentialling, results demonstrated variations in FET-PET1-derived BTV in 25/72 (34.7%) - 13 minor and 12 major.Currently, 42 of 112 participant FET-PET1 with BTV delineation cases across 10 sites have undergone central review, with 7/42 (16.7%) requiring resubmission. Reasons for resubmission/protocol deviation included incorrect imaging sequence selection within the MiM workflow (n=3), Static GTV overcontouring (n=3) and dynamic volume of interest change in size/position during MiM workflow use (n=1). CONCLUSION The FIG trial will complete recruitment in 2024 with analyses planned at one year post CRT completion. Despite improvements in resubmission rates compared to the credentialling phase, central review of prospective FET-PET1-derived BTV delineation remains important in ensuring protocol adherence. The FIG study is the largest prospective multi-site study of its kind addressing FET-PET’s impact on adjuvant radiation planning and its role in management of pseudoprogression and prognostication.
QLTI-04. UPDATE ON HIGH-GRADE GLIOMA PATIENTS TREATED WITH TTFIELDS FROM NANFANG HOSPITAL IN CHINA
Authors: Haojie Zheng, Tianshi Que, Guozhong Yi, Zhiyong Li, Shanqiang Qu, Peidong Zhang, Xi Yuan, Yajuan Wang, Junlu Liu, Jing Nan, Ting Liu, Haiyan Xu, Songtao Qi, Guanglong Huang
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE Tumour-treating fields (TTFields) have changed the first-line clinical practice of glioblastoma worldwide due to their promising therapeutic efficacy. The aim of this study was to investigate the clinical efficacy of TTFields therapy for HGG in Nanfang Hospital, China. In 2023 ASNO we reported PFS.Now we reporte update about OS from our single center study. METHODS From January 2019 to December 2022, a total of 25 patients with newly diagnosed HGG (ndHGG) treated with TTFields were retrospectively included in our study. Among these patients, 9 patients received concurrent radiochemotherapy in combination with TTFields and 16 patients received non-concurrent chemoradiotherapy in combination with TTFields. The primary endpoint of the study was mPFS and mOS (Kaplan-Meier method used to estimate PFS and OS survival curves). Secondary endpoint was the influences about KPS score in PFS and OS. RESULTS The 25 ndHGG patients treated with TTFields included nine males and sixteen females with a mean age of 47.1 years (12-68). Gross total resection (GTR) was performed in eighteen patients. Twenty-one patients were IDH wild type, eleven patients showed methylation of the MGMT promoter. Followed up until January 2024, the median PFS was 13.3 months [95% CI: 11.33-15.2] with TTFields combined and 4.0 months (95% CI, 3.8-4.4) without TTFields treatment in EF-14.Median OS was 26.53 months [95% CI:19.47-33.57] with TTFields and 16.0 months (95% CI, 3.8-4.4) control in EF-14. In the KPS stratification, OS was 27.5 months (95% CI: 22.95-32.1) vs 4.3 months (95% CI: 0-11.2), p=0.0001. The OS of patients with concurrent chemoradiotherapy combined with TTFields vs. without concurrent chemoradiotherapy combined with TTFields was 26.5 months (95% CI: 24.33-28.7) vs 21.2 (95% CI: 3.1-39.3) months, p=0.59. CONCLUSIONS TTFields therapy is an effective treatment for HGG. In this study the addition of TTFields resulted in a statistically significant improvement in PFS and OS.
CTIM-34. EFFECTS OF NEOADJUVANT IMMUNE CHECKPOINT INHIBITION ON PEDIATRIC AND ADULT HIGH-GRADE GLIOMAS
Authors: Hadar Keren-Gill, Gilbert Herrera, Shivani Baisiwala, Lauren Markus, Lu Sun, Richard Everson, Michal Yalan Oren, Dinisha Govender, Ashley Margol, Susan Chi, Michael Prados, Cassie Kline, Sabine Mueller, Tom Belle Davidson, Robert Prins
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas (HGG) are lethal tumors with few long-term survivors affecting adult and pediatric patients. Studies investigating immune checkpoint inhibition (ICI) suggest administration of neoadjuvant anti-PD1 blockade (neo-aPD1) enhances local and systemic anti-tumor responses. This data is supported by increased T cell density in the tumor and proportion of cytotoxic T cells in peripheral blood. In a previous randomized clinical trial, neo-aPD1 improved survival in adult with recurrent glioblastoma. In this study, we utilized multiplex immunofluorescence (mIF), and single-cell RNA sequencing (scRNA-seq) to investigate the effects of neoadjuvant ICI on the TME and compare between pediatric and adult populations. Tissue samples from adult patients with recurrent GBM treated with neo-aPD1 (n=22) or adjuvant only therapy (n=5) were obtained from our UCLA off-label neo-PD1 study. Tissue samples were also obtained from pediatric patients with recurrent/progressive HGG treated with neoadjuvant ICI from the ongoing Pediatric Neuro-Oncology Consortium study PNOC19. Samples included diagnostic tissue from two patients and on study surgery tissue from four patients. All tissue samples were subjected to mIF and underwent imaging analysis to assess immune cell infiltration by quantifying lymphoid and myeloid cell densities across the two treatment groups. Our preliminary findings elucidated a trend of higher T cell infiltration in adult neoadjuvant compared to adjuvant-only treated patients (median density 58.11 vs 15.15 T-cells/mm2). Compared to their adult counterparts, neoadjuvant ICI treated pediatric patients had even more robust total T cell infiltration (median density 268.10 vs 58.11 T-cell/mm2, pediatric vs adult respectively). scRNA-seq analysis revealed a greater enrichment of monocytic macrophages in the pediatric population compared to tissue resident microglia in the adults. This early data requires analysis of additional samples to better understand differences in the anti-tumor immune response between adult and pediatric recurrent/progressive HGG patients.