tbuckley/cabot-search huggingface dataset:
CTIM-04. MODULATION OF THE INTRATUMORAL IMMUNE MICROENVIRONMENT BY LOCAL THERAPY WITH NATURAL KILLER CELLS ENGINEERED WITH A HER2-TARGETED CHIMERIC ANTIGEN RECEPTOR IN COMBINATION WITH SYSTEMIC ANTI-PD-1 CHECKPOINT INHIBITION IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Michael Burger, Elisabeth Ehrend, Florian Straßheimer, Pinar Cakmak, Harald Krenzlin, Philipp Elleringmann, Pia Zeiner, Stefanie Herkt, Isabel Poschke, Jadranka Macas, Katharina Weber, Jonathan Schupp, Jennifer Lun, Corinna Opitz, Bastian Roller, Patricia Manns, Svenja Klinsing, Stella Breuer, Stephanie Hehlgans, Seo-Youn Lee, Iris Mildenberger, Gleb Ludmirski, Julian Hermann, Elvira Müller, Marc Schmitz, Marcus Mehlitz, Christian Senft, Patrick Harter, Michael Rieger, Franz Rödel, Marcus Czabanka, Miriam Ratliff, Michael Platten, Christel Herold-Mende, Florian Ringel, Eva Herrmann, Elke Hattingen, Yvonne Reiss, Lukas Bunse, Halvard Bonig, Karl Plate, Marie-Therese Forster, Torsten Tonn, Winfried Wels, Joachim Steinbach
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GB) is characterized by a marked immunosuppressive tumor microenvironment. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. 6 patients were treated with repetitive doses of CAR-NK cells as monotherapy and 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. In three of those, we were able to implement a biopsy-treat-resect-treat strategy. After initial biopsy, combination treatment was initiated before planned tumor resection, enabling analysis of the transformation of the tumor immune microenvironment by highplex multispectral fluorescent analyses and cytokine quantification. None of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Profound alterations of the immune cell distribution in the cerebrospinal fluid (CSF) and in the tumor were observed. In CSF sampled from the resection cavity, combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts. In post-treatment tissue samples, we observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. The three patients treated following the biopsy-treat-resect-treat strategy achieved a median progression-free survival (PFS) of 24 weeks, compared to 10 weeks for patients with upfront resection. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted.
EPID-11. RATES OF CRANIOTOMIES FOR BRAIN METASTASES AFTER INTRODUCTION OF IMMUNOTHERAPY
Authors: Isabelle Pelcher, Sabrina Begley, Sanjeev Sreenivasan, Yonah Ziemba, Isabella Travaglia, Avi Ratra, Michael Schulder
Journal: Neuro-Oncology (2024)

Abstract Immunotherapy has revolutionized the treatment paradigm for patients with brain metastases and has been found to prolong overall survival. We sought to determine whether rates of craniotomies for the treatment of brain metastases has decreased since the introduction of immunotherapy into routine treatment regimens. Pathology records were queried at our institution from 2011-2022 to include all patients surgically treated for brain metastases. A total of 885 samples from 789 unique patients were analyzed. National data was queried from the NSQIP database from 2011-2022 to include patients surgically treated for brain metastases with a total of 14,494 cases. A Craniotomy for Metastases Index (CMI) was generated to reflect the total number of craniotomies performed over time. The most common institutional primary cancers were lung (46.1%), breast (17.4%), and gastrointestinal (10.1%), with the most common lung cancers being adenocarcinoma (57.11%) and non-small cell carcinoma (11.52%). The institutional CMI demonstrated a non-significant decrease in the number of craniotomies (R2=0.0545, p=0.46) across all time ranges, as well as no significant change in CMI when comparing rates from 2011-2016 and 2017-2022 (p=0.37). The national CMI demonstrated a significantly positive slope of 0.03 (R2=0.544, p=0.006), as well as a significant increase (p=0.005) in craniotomies when comparing rates from 2011-2016 and 2017-2022. Despite the growing use and efficacy of immunotherapy in the treatment of brain metastases and increasing overall survival, the rates of craniotomies had no change institutionally and increased nationally. Several reasons for these findings may include: longer overall survival of patients with systemic cancer can lead to the development of metastatic brain tumors later in their disease course, improvement of surgical techniques making resection safer, and variable response of patients to stereotactic radiosurgery (SRS). Further studies should be conducted to determine the effect of SRS on these findings. Surgical resection remains the mainstay in the treatment of brain metastases.
EPCO-35. GENOMIC CHARACTERIZATION OF GROWTH HORMONE SECRETING PITUITARY ADENOMAS
Authors: Hasan Alanya, Kanat Yalcin, Brian Hilton, Batur Gultekin, Ketu Mishra-Gorur, Declan McGuone, Murat Gunel, Sacit Bulent Omay, Zeynep Erson-Omay
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pituitary adenomas (PAs) are the second most common brain tumors in adults with prevalence ranging from 80 to 100 per 100,000 individuals. Of these, 9% to 14% are growth hormone (GH)-secreting PAs. While recurrent somatic GNAS mutations are identified in approximately half of sporadic GH-secreting PAs, the remaining cases are not well-characterized. This study aims to expand the genomic profile of GH-secreting PAs and explore correlations between molecular and clinical features. METHODS Whole exome sequencing (WES) was performed on 19 tumors with matching blood samples from consenting patients, achieving mean coverages of 262.74X for tumor samples and 112.43X for blood samples. Somatic variants, including single nucleotide variants (SNVs), short insertions/deletions (INDELs), and copy number variations (CNVs), were identified, and analyzed using protocols established by our institution. Genomic instability was assessed by calculating the percentage of the genome displaying loss-of-heterozygosity (LOH). Clinical data were collected and analyzed to establish genomic correlations. RESULTS The cohort comprised 19 GH-secreting PAs, with a mean age of 46 years at surgery, and was predominantly female (78.9%). The cohort was enriched for macroadenomas, with a mean tumor size of 18.4 mm. WES revealed a mean somatic mutation count of 20.4 (range 7-79), with 47% of cases harboring recurrent GNAS mutations. The mean alteration by LOH across the cohort was 11.13% (range: 0-44.80%) and did not show a statistically significant difference between cases with GNAS mutations and GNAS-wildtype cases (7.71% vs. 14.21%, respectively). Chromosomes 3, 8, 16, 22q were frequently affected by CNV/LOH events. CONCLUSION Comprehensive genomic characterization, including assessment of genomic instability through CNV/LOH analysis, is critical for better understanding the pathogenesis of GH-secreting PAs. This study underscores the importance of detailed genomic profiling in larger cohorts for improving the diagnosis and management of these tumors.
CTNI-57. REAL-WORLD EVIDENCE OF THE FREQUENCY OF POST-SURGICAL INITIAL OBSERVATION IN PATIENTS WITH IDH-MUTANT GLIOMA
Authors: Michal Nisnboym Ziv, Tarun Bhagnani, Gary Binder, Christelle Chacar, Ravi Potluri, Timothy Werwath, Jonathan Dewey, Katherine Peters
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND After initial resection of IDH-mutant gliomas, initial observation is an option for low-risk patients, to postpone potential therapy-related toxicities without impacting survival. Since NCCN guidelines for risk stratification are considered controversial, we aimed to assess the frequency of initial observation in IDH-mutant gliomas using real-world evidence in the US. METHODS We evaluated Optum claims from 2016-2021 of patients age ≥12 with ICD-10 codes for incident glioma. Since ICD-10 does not distinguish IDH-mutant from IDH-wild type (GBM) gliomas, we excluded patients with factors indicative of GBM (age&amp;gt;60/ hypofractionated RT/ carmustine wafer/ tumor-treating fields) to create a baseline cohort. We then evaluated the subgroup age &amp;lt;40 (&amp;lt;40 cohort), who have higher IDH-mutant incidence. To distinguish initial observation from surgical recovery, we assessed time from index surgery to first intervention. When 90% of first interventions had occurred those still without intervention were considered to undergo initial observation. RESULTS The baseline and &amp;lt;40 cohorts comprised 5404 and 646 patients, respectively. In the baseline cohort, 56% had intervention by day 90 (most commonly concurrent chemoradiation); peak intervention rate was 60%. Initial observation rate was 44%. In the &amp;lt;40 cohort, 47% had an intervention by day 90; peak intervention rate was 52%. Initial observation rate was 53%. CONCLUSIONS In both cohorts ≥90% of patients with likely IDH-mutant gliomas not initiating treatment within 3 months post-surgery continued in active observation. Initial observation rates were 44-53%, well above the levels we had expected based on NCCN guidelines. The cohorts likely include some GBM patients, for whom observation is unaccepted, and therefore these rates may understate actual initial observation rates for IDH-mutant glioma patients. These findings suggest that clinicians and patients have chosen initial observation over existing treatments, evincing a need for additional treatment options for this younger group of patients with considerably long life expectancy.
TMET-35. UPREGULATION OF THE URIDINE SALVAGE PATHWAY IN MESENCHYMAL GLIOBLASTOMA STEM-LIKE CELLS
Authors: Tuvshintugs Baljinnyam, Mark L Sowers, Bruce Chang-Gu, Hui Tang, Jason L Herring, Kangling Zhang, Lawrence C Sowers
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma is a heterogenous tumor comprised of multiple molecular subtypes of cancer cells and cancer stem-like cells. Of particular importance are the cancer stem-like cell niche population as they are believed to be more resistant to existing therapies and re-seed the tumor following initial response to standard-of-care treatment. To better understand glioblastoma stem-like cells we completed an untargeted proteomic analysis of 35 patient derived glioblastoma stem cell lines. This revealed an increase in several important proteins involved in the uridine salvage pathway, in the mesenchymal subtype. A subset of these proteins, including ecto-5’-nucleotidase (NT5E/CD73), uridine phosphorylase (UPP1), phosphoglucomutase-2-like-1 (PGM2L1), nicotinamide phosphoribosyltransferase (NAMPT), and nicotinamide N-methyltransferase (NNMT), suggest an augmented pathway for utilization of UMP and uridine as a fuel source and to replenish NAD+. Uridine and UMP are present in human serum and are enriched in the tumor microenvironment, providing a sustainable resource to resupply the tumor. The upregulation of this pathway was validated in established cell lines and orthogonal patient-derived xenograft cell lines not included in the proteomics study. Further work is underway to selectively inhibit or exploit this pathway with small molecule inhibitors.
SURG-08. A PHASE III RANDOMIZED TRIAL OF GROSS TOTAL RESECTION VERSUS POSSIBLE RESECTION OF FLAIR HYPERINTENSITY LESION ON MR IMAGE FOR NEWLY DIAGNOSED SUPRATENTORIAL GLIOBLASTOMA (JCOG2209)
Authors: Yukihiko Sonoda, Yuta Sekino, Junki Mizusawa, Ichiyo Shibahara, Keita Sasaki, Tetsuya Sekita, Mayumi Ichikawa, Hiroshi Igaki, Manabu Kinoshita, Junji Shibahara, Koichi Ichimura, Yoshiki Arakawa, Yoshitaka Narita
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Complete resection of contrast-enhanced lesion (gross total resection: GTR) without severe neurological deficits has been generally accepted as the goal of surgery. However, it remains unclear if additional resection of surrounding FLAIR hyper-intense lesion combined with GTR (FLAIRectomy) has survival advantage of primary glioblastoma patients. Purpose: Multicenter, open-label, randomized phase III trial was commenced to confirm the superiority of FLAIRectomy to GTR alone followed by radiotherapy with concomitant and adjuvant temozolomide in terms of overall survival (OS) for primary glioblastoma IDH-wildtype patients. This trial investigates not only survival but also postoperative neurological and neurocognitive deficits in detail. METHODS We assumed a 2-year OS of 50% in the GTR arm and expected a 15% improvement in the FLAIRectomy arm. A total of 130 patients is required with a one-sided alpha of 5%, power of 70%, and will be accrued from 49 Japanese institutions in 4 years and follow-up will last 2.5 years. Patients 18-75 years of age will be registered and randomly assigned to each arm with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, proportion of National Institutes of Health stroke scale preservation, proportion of mini-mental state examination preservation and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in May 2023. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in July 2023. DISCUSSION If FLAIRectomy is superior to GTR alone, aggressive surgery will become a standard surgical treatment for glioblastoma with resectable contrast-enhanced lesion. Trial registration: Registry number: jRCT1031230245. Date of registration: 19/July/2023. Date of first participant enrollment: 28/July/2023. Funding for this study is provided by National Cancer Center Research and Development Fund (2023-J-03).
CTNI-55. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN NEWLY DIAGNOSED, MGMT-UNMETHYLATED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Nader Sanai, Yoshie Umemura, Siddhi Desai, Tigran Margaryan, Jennifer Molloy, Costanza LoCascio, Mackenna Elliott, Jocelyn Harmon, Amy Hong, Ernesto Luna Melendez, John Wanebo, Kelly Braun, William R Kennedy, Michael Garcia, Wonsuk Yoo, Artak Tovmasyan, An-Chi Tien, Shwetal Mehta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ATM inhibition is hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair. This Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed and recurrent GBM patients (NCT05182905). METHODS All patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hrs following the final dose (120/300mg for nGBM and 400mg for rGBM). Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. A PK ‘trigger’ determined eligibility for Phase 1b and patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) were eligible for therapeutic dosing of AZD1390 plus radiotherapy. RESULTS Thirty nGBM patients and twenty-nine rGBM patients were enrolled. Forty-eight out of the forty-nine evaluable patients exceeded the PK threshold and qualified for therapeutic dosing. The mean unbound concentrations of AZD1390 in Gd-nonenhancing tumors of both nGBM and rGBM patients were significantly above the threshold at all dose levels and time intervals. Following 5Gy ex vivo radiation of surgical specimens, pRAD50 expression was significantly suppressed in AZD1390-treated patients compared to untreated controls. To date, 6 MGMT-unmethylated nGBM patients and 15 rGBM patients were enrolled in the Phase 1b component of the study, with median clinical follow-up of 7.0 months. Median PFS and OS have not been reached in the nGBM population. Median OS for rGBM patients was 15.4 months. CONCLUSION AZD1390 is well-tolerated in both newly-diagnosed and recurrent GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and suppressing radiation-induced increase in pRAD50 levels. These data are the first to demonstrate AZD1390-mediated PD and PK responses in nGBM and rGBM patients. Clinical outcomes data are maturing and will be reported.
CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)
Authors: Eugene Hwang, Lindsey Kilburn, Duane Mitchell, Tong Lin, T Y Poussaint, Giles Robinson, Amar Gajjar, Alicia Lenzen, Kathleen Dorris, Nathan Robison, Jason Fangusaro, Maryam Fouladi, Arzu Onar-Thomas, Ira Dunkel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.
BIOM-11. PROGNOSTIC VALUE OF H3K27ME3 AND EZH2 IN ASTROCYTOMA, IDH-MUTANT
Authors: Shumpei Onishi, Fumiyuki Yamasaki, Vishwa Jeet Amatya, Ushio Yonezawa, Akira Taguchi, Iori Ozono, Novita Ikbar Khairunnisa, Yukari Go, Yukio Takeshima, Nobutaka Horie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND H3K27 trimethylation (H3K27me3), catalyzed by EZH2, regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a surrogate marker in pathology for diffuse midline glioma, ependymoma. However, the clinical value of H3K27me3 and EZH2 in astrocytoma, IDH-mutant has not been reported. The aim of this study was to evaluate the clinical significance of H3K27me3 and EZH2 in astrocytoma, IDH-mutant. METHODS A total of 30 patients with astrocytoma, IDH-mutant treated at our institute were included. The patients were divided into 2 groups according to the expression of immunohistochemistry (IHC) for H3K27me3. The following factors were analyzed; age, WHO grade, IHC for EZH2, CDKN2A status, ki67-index and extent of resection. The CDKN2A status was diagnosed by IHC for MTAP and was confirmed by NGS-based CGP test in some cases. Kaplan–Meier analysis and Cox regression analysis were performed to analyze overall survival (OS) and progression-free survival (PFS). RESULTS According to WHO classification 2021, astrocytomas were classified as follows: WHO grade2: 20 cases, grade 3: 2 cases, grade 4: 8 cases. Seventeen patients were identified as H3K27me3 positive, while fourteen patients were classified as H3K27me3 negative. The proportion of WHO grade 3 or 4 and ki-67 index were significantly higher in the H3K27me3 positive group (p=0.0011, 0.0036, respectively). OS and PFS were significantly longer in H3K27me3 positive group (p=0.0379, 0.0025). Furthermore, in the analysis of WHO grade 2/3, double-positive expression of H3K27me3 and EZH2 showed significantly shorter PFS and OS than the other group (p=0.0114 and 0.0068, respectively). In Cox regression analysis, H3K27me3 showed the highest likelihood ratio for OS (p=0.01061). CONCLUSIONS In Astrocytoma, IDH-mutant, the H3K27me3 positive group showed poor prognosis than H3K27me3 negative group. In addition, patients with double-positive expression of H3K27me3 and EZH2 demonstrated more unfavorable prognosis. H3K27me3 and EZH2 could be prognostic markers for astrocytoma, IDH-mutant.