tbuckley/cabot-search huggingface dataset:
MDB-49. OUTCOMES OF SONIC HEDGEHOG (SHH) MEDULLOBLASTOMA (MB) IN CHILDREN AND ADULTS TREATED WITH RISK-ADAPTED THERAPY ON A PROSPECTIVE INTERNATIONAL PROTOCOL (SJMB12)
Authors: Amar J Gajjar, Brent Orr, David Ellison, Lucie Lafay-Cousin, Jane Minturn, Michael Fisher, Anne Bendel, Eugene Hwang, Jeffrey Murray, Daniel Landi, Amy Smith, Nicholas Gottardo, Santhosh Valvi, Tim Hassal, Jennifer Elster, Sebastian Perrault, Vijay Ramaswamy, Sonia Partap, Stephen Laughton, Richard Cohn, Murali Chintagumpala, Geoffrey McCowage, Jordan Hansford, Michael Sullivan, Elias Sayour, Daniel Bowers, Asher Marks, Jie Huang, John Lucas, Christopher Tinkle, Soniya Pinto, Asim Bag, Noah Sabin, Paul Northcott, Paul Klimo, Thomas E Merchant, Arzu Onar-Thomas, Giles W Robinson
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND SJMB12 (NCT01878617) was among the first protocols to treat newly diagnosed MB incorporating molecular subgrouping. METHODS Tumors were subtyped and TP53 mutation assessed via immunohistochemistry. SHH patients were grouped into 2 strata: S1 (GTR/NTR; M0) and S2 (residual &amp;gt; 1.5 cm2; MYC/MYCN amplification; M+). Treatment consisted of maximal surgical resection followed by risk adapted craniospinal irradiation (CSI) (S1 = 23.4 Gy CSI; S2= 36); 54 Gy primary site. Patients then received 4 cycles of chemotherapy consisting of Vincristine 1 mg/m2 on Day 1 and Day 8; Cisplatin 75 mg/m2 on Day 1 and Cyclophosphamide 1.5 gm/m2 on Day 2 and 3 with Mesna and IV fluid support. PEG Filgrastim was administered on Day 4. Skeletally mature pts (males with bone age ≥ 17 yrs.; females with bone age ≥ 15 yrs.) were also treated with the smoothened inhibitor Vismodegib for 12 months. RESULTS Of the 660 patients accrued from 2013-2022, 110 were SHH (107 evaluable, 62 in S1 and 45 in S2). Median age was 12.2 yrs. (3.1-39.7) and 67 were males. 98 patients had GTR/NTR, 31 had M+ disease and 63 had nodular desmoplastic histology. TP53 mutation was detected in 7 (11.5%) S1 and 18 (40%) S2 pts. 5-year EFS for S1 and S2 were 84.5 ± 6.4% and 61 ± 11.5%, respectively. Five-year EFS of the S1 was 91.7 ± 5.4% and 28.6 ± 13.9% for TP53 wildtype and TP53 mutant cases, respectively, and 84.2 ± 10.1% and 25.0 ± 21.7% in the S2 cohort. CONCLUSION Patients with low-risk SHH MB lacking TP53 mutation have excellent survival and may be considered for therapy reduction. TP53 mutation, with or without M+ disease, leads to a dismal outcome that needs novel therapy for cure.
EPID-09. CONGENITAL CENTRAL NERVOUS SYSTEM NEOPLASMS: A RETROSPECTIVE REVIEW FROM THE<i>MARGARET HACKETT FAMILY PROGRAM CONSORTIUM</i>
Authors: Carolina Lopes, Amanda M Mosher, Joanna E Papadakis, Dylan Keusch, Kelsey Largen, Daniel Weber, Jesse Huang, Bakhtiar Yamini, David Bauer, Moise Danielpour, Christina Sayama, Lissa Baird
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Congenital intracranial neoplasms are a heterogeneous group of lesions that account for &amp;lt;2% of pediatric CNS tumors. Current understanding of histopathologic and survival outcomes in this population is limited. METHODS Pediatric patients (&amp;lt;3-years) with congenital neoplasms were retrospectively evaluated across five institutions. Demographic, prenatal care, clinical presentation, histopathologic characteristics, operative and adjuvant therapies, and survival outcomes were collected. RESULTS 323 patients met inclusion. The mean age at diagnosis was 1.5-years. Six patients were conceived through IVF. Eleven families reported abnormal prenatal ultrasounds, although only six were diagnosed prenatally. The most common histopathologies included low-grade astrocytoma (30.6%), ependymoma (15.8%), ATRT (11.5%), medulloblastoma (8.0%), and high-grade astrocytoma (2.8%). 48.9% of patients had low-grade neoplasms, and a third of patients (33.1%) had high-grade tumors. Patients commonly presented with hydrocephalus (59.1%), emesis (34.7%), ocular abnormalities (20.4%), macrocrania (18.0%), lethargy (14.6%), developmental delays (12.7%), and irritability (11.8%). All patients received surgical resection: 55.4% received gross-total (GTR) and 20.4% received subtotal resection. Concurrent treatment with adjuvant therapies occurred in a subset of patients, with 52.9% of patients receiving chemotherapy, 27.2% undergoing radiation, and 6.2% participating in a clinical trial. Patients with low-grade tumors had a rate of 88% progression-free (PFS) at 1-year, 74% PFS at 3-years, and 64% PFS at 5-years post-operative. Patients with high-grade neoplasms had worse PFS, with estimates at 59%, 40%, and 37% at 1-, 3-, and 5-years, respectively. There was statistically significant differences in PFS between patients with high- and low-grade neoplasms (p&amp;lt;0.0001). CONCLUSIONS This series consisted of very young pediatric patients across five participating institutions with diverse histopathologies that vary in frequency relative to the entire pediatric population. Lesions were rarely detected prenatally, despite their young age at diagnosis. GTR occurred in half of patients and subsequent management with adjuvant therapies was common in both sub-totally resected low-grade lesions and high-grade tumors.
IMMU-21. B7-H3 NANOBODY CAR-T CELL THERAPY IN PEDIATRIC GLIOBLASTOMA
Authors: Mia Fanuzzi, Mohit Pratap Singh, Mariela Puebla, Allison Cole, Dan Li, Mitchell Ho, Anandani Nellan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Immunotherapy is a developing but challenging field of research for the treatment of central nervous system malignancies. Chimeric antigen receptor (CAR)-T cell therapy has been effective in treating hematologic malignancies, but that success has not been clinically translated to solid tumors in children. B7-H3 has been identified as a promising immunotherapy target as it is highly expressed in pediatric glioblastoma and correlates with tumor progression and poor prognosis. We aim to evaluate a nanobody-based CAR-T cell therapy that binds B7-H3 with high affinity and hypothesize that anti-B7-H3 nanobody CAR-T cells can effectively kill B7-H3-expressing tumor cells. METHODS B7-H3 nanobodies were isolated from camel phage libraries and cloned into lentiviral CAR-T cell constructs. Human T cells were transduced by lentivirus to express CAR on the surface. Nanobody CAR-T cell functionality was evaluated by an impedance-based cytotoxicity assay and cytokine release was measured by ELISA. CAR-T avidity was quantified by the Lumicks z-Movi assay. In vivo studies are evaluating the efficacy of B7-H3 CAR-T cells in an orthotopic glioblastoma model in immunodeficient mice. Mice were treated with B7-H3 CAR-T cells by intracerebroventricular or intravenous delivery. RESULTS We confirmed high expression of B7-H3 on the surface of three pediatric glioblastoma cell lines by flow cytometry and Quantibrite staining. We confirmed effective killing of B7-H3-expressing tumor cells and the release of high levels of cytokines. B7-H3 nanobody CAR-T cells were observed to have high avidity compared to control CAR-T cells. In vivo studies are currently ongoing and treatment response will be evaluated by luminescence imaging and endpoint histologic analysis. CONCLUSION We have shown that B7-H3 nanobody CAR-T cells demonstrate significant preclinical efficacy. It is critical to study CAR-T cell therapy in immunocompetent in vivo models for further development and clinical application.
GCT-21. MULTINATIONAL ANALYSIS OF PEDIATRIC RELAPSED/REFRACTORY CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Mohammad Hatim Abu-Arja, Mary Claire McGlynn, Mohammed Saad Zaghloul, Ahmed Elhemaly, Kelsey Bertrand, Ammar Gajjar, Rebecca Ronsley, Andrea M Cappellano, Natalia Dassi, Malgorzata Czogala, Richard Graham, Truman Knowles, Sabine Meuller, Girish Dhall, Sumanth Nagabushan, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor prognosis. We explored prognostic factors to guide the management of these patients. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. Data were summarized using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS We identified 31 patients from eight centers. The median age at initial diagnosis was 11 years (interquartile range (IQR): 9-15.3). Twenty patients (64.5%) suffered a relapse, and 11 patients (35.5%) had refractory disease. The median follow-up time since relapse/progression was 17.5 months (range:1-295). The median time to relapse/progression was 12.1 months (IQR: 5.5-27.5). Ten patients (32.3%) received high-dose chemotherapy (HDCx) with stem cell rescue. Sixteen patients (51.6%) received re-irradiation at relapse/progression. Nine patients (29%) achieved complete remission (CR). Ten patients (32.3%) were alive at the time of the last follow-up. Among the ten survivors, the median serum and cerebrospinal fluid (CSF) alpha-fetoprotein levels were 2.3 ng/dl (range: 0-17) and 2.1 ng/dl (range: 0-55), respectively, the median serum and CSF beta-human chorionic gonadotropin were 23 IU/L (0-168) and 139 IU/L(0-601), none underwent gross total resection, eight received HDCx, and seven received radiotherapy (craniospinal irradiation (n=6), abdominal radiotherapy (n=1)). HDCx (OR=19.8, 95%CI: 2.7-145.7; p=0.01) and achieving CR at the end of relapse treatment (OR=160, 95%CI: 8.9-2880.5; p=&amp;lt;0.001) were associated with a survival benefit. Re-irradiation (OR=3.3 95%CI: 0.53-20.9; p=0.24) was not associated with a survival benefit. CONCLUSIONS A subset of patients with relapsed NGGCTs are salvageable at relapse. HDCx and achieving CR at the end of relapse therapy were associated with a survival benefit. More studies are required to identify these patients who would benefit from salvage therapy.
GCT-06. THE OUTCOMES OF PATIENTS WITH DISSEMINATED GERMINOMA TREATED ON ACNS0232: A REPORT FROM THE CHILDREN’S ONCOLOGY REPORT
Authors: Margaret Shatara, Subodh Selukar, Tong Lin, Amar Gajjar, Bernadine Donahue, Sarah Leary, Maryam Fouladi, Jeffrey C Allen, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Central nervous system (CNS) germinomas are curable with craniospinal irradiation (CSI). However, concerns about long-term sequelae led to investigations into neoadjuvant chemotherapy. The ACNS0232 study, a phase III trial, evaluated the efficacy of neoadjuvant chemotherapy followed by response-based radiotherapy (RT) in patients with germinomas. METHODS Patients aged 3-21 years with newly-diagnosed histologically-confirmed germinoma were randomized to standard RT alone (Regimen A: 24 Gy CSI with a boost of 21 Gy) or neoadjuvant chemotherapy followed by response-based RT (Regimen B: 2 cycles of carboplatin/ etoposide, and if not in complete response (CR), two additional cycles of of cisplatin/ cyclophosphamide were administered followed by 21 Gy CSI with boost of 9 Gy). The study objectives included comparing event-free (EFS), overall survival (OS) and evaluating response to pre-RT chemotherapy. RESULTS Twenty-two patients (10 in Regimen A, 12 in Regimen B) were randomized between January 2007 and May 2009, including 13 with disseminated disease (5 in Regimen A, 8 in Regimen B). The study closed early due to low accrual. The median study follow-up time was 5.8 years. The 5-year EFS estimates were 0.89 (95% CI 0.47, 0.98) for Regimen A and 0.92 (95% CI 0.47, 0.99) for Regimen B. Regimen B was well-tolerated and demonstrated a 72.7% CR rate. CONCLUSION Despite the premature closure of the study, ACNS0232 provides valuable insights into the role of neoadjuvant chemotherapy with response-based RT in the treatment of disseminated germinoma. However, it is crucial to acknowledge the limitations of drawing conclusions with such a small sample size. The COG oncology community was not supportive of the proposed phase 3 design, but there is value in expanding the limited experience using Regimen B in a single arm phase 2 study to validate the safety and efficacy of neoadjuvant chemotherapy strategies in patient’s with disseminated CNS germinoma.
IMMU-22. B7-H3 NANOBODY CAR-T AND SOLUBLE TREM2 GENETICALLY ENGINEERED MYELOID CELL THERAPY IN MURINE SYNGENEIC GLIOBLASTOMA
Authors: James C Cronk, Rajaa El Meskini, Mia Fanuzzi, Devon Atkinson, Debbie Householder, Mariela Puebla, Laura Bassel, Brendan Ball, Emily San Andres Montalvan, Dan Li, Sabina Kaczanowska, Mitchell Ho, Rosandra N Kaplan, Zoe Weaver Ohler, Anandani Nellan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Myeloid immunosuppression can be a major impediment to CAR-T cell therapy for CNS tumors. Importantly, CAR-T cells are often evaluated in immunocompromised mice which cannot accurately recapitulate the tumor immune response or tumor microenvironment. CNS tumor macrophages express TREM2, an important driver of immunosuppression. This study combines B7-H3 targeting nanobody CAR-T cells which are cross reactive in humans and mice (currently being evaluated for clinical development) with genetically engineered myeloid cells (GEMys) expressing soluble TREM2 (sTREM2) in a syngeneic mouse model of glioblastoma (GBM), with the aim of blocking TREM2-mediated immunosuppression to enhance CAR-T cell function. METHODS Syngeneic murine GBM, designed to mimic human GBM and generated at the Center for Advanced Preclinical Research (CAPR), was used for all studies. B7-H3 nanobody CAR-T cells were generated from mouse splenic T cells. In vitro tumor killing assays were performed by xCELLigence. sTREM2 GEMys were generated from bone marrow progenitor cells using lentiviral transduction. For in vivo studies, mice underwent orthotopic implantation of tumors and placement of an MRI-compatible, permanent catheter-port system for serial intracerebroventricular (ICV) administration of cell therapies. Mice were treated with CAR-T and/or GEMy therapies, evaluated weekly for tumor burden by MRI, and were monitored for survival. RESULTS Syngeneic GBM expression of B7-H3 was confirmed by flow cytometry, immunofluorescence, and western blot. B7-H3 nanobody CAR-T cells demonstrated effective killing of GBM by xCELLigence. sTREM2 GEMys were successfully generated and confirmed to produce sTREM2. Cell therapies were successfully infused ICV via the implanted catheter-port system, demonstrating safety and feasibility of this model for serial ICV cellular therapy. CONCLUSIONS B7-H3 nanobody CAR-T cells were validated against syngeneic GBM, and we have demonstrated safety and feasibility of ICV catheter administration of cellular therapies in vivo. Future studies will continue to evaluate in vivo timing and efficacy of CAR-T and GEMy therapy.
MDB-44. MIR-106B-5P DEPLETION IN GROUP 4 METASTATIC MEDULLOBLASTOMA SEVS FINE-TUNES MMP-2 ACTIVATION VIA DIFFERENTIAL TIMP-2 PROTEIN ABUNDANCE
Authors: Connor T Levers, Hannah K Jackson, Ian D Kerr, Federico Dajas-Bailador, Beth Coyle
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Small Extracellular Vesicles (sEVs) are major intercellular communicators, with growing evidence of a role in establishing favourable metastatic niches during cancer progression. We have shown that, relative to their paired primary counterpart, Group 4 (Grp4) metastatic Medulloblastoma (MB) cell-lines release significantly more sEVs with increased functionally active MMP-2 on their surface, resulting in enhanced extracellular matrix degradation and subsequently increased cell invasiveness. METHODS Transcriptomic analysis of sEV microRNA cargoes derived from metastatic/recurrent and primary cell-line and patient CSF samples, followed by microRNA target prediction of differentially abundant microRNAs using TargetScan and miRDB was conducted. Patient dataset analysis was used to confirm microRNA target mRNA expression levels. Finally, microRNA inhibition followed by RT-qPCR or invasion assays were used to quantify changes at the gene and functional level. RESULTS Transcriptomic analysis demonstrated &amp;gt;75% miR-106b-5p depletion in Grp4 MB metastatic sEVs compared to their primary sEV counterparts derived from cell-line and patient CSF samples. This microRNA is predicted to target TIMP-2, which plays a crucial role in MMP-2 activation. We confirmed TIMP-2 to be upregulated in paired metastatic Grp4 tumours relative to their primary counterpart using a publicly available patient dataset. Following miR-106b-5p inhibition in the primary cell-line, RT-qPCR analysis and invasion assays determined the existence of a complex functional response, with increasing TIMP-2 gene expression leading to decreasing invasiveness. This suggests a delicately balanced process where TIMP-2 overabundance can ultimately impede MMP-2 activation. In support of this, analysis of patient datasets showed intermediate TIMP-2 gene expression amongst Grp3/4 patients compared to less frequently metastatic subgroups. CONCLUSIONS Our data support the hypothesis that sEV-derived miR-106b-5p regulates enhanced ECM degradation through fine-tuning MMP-2 activation via differential TIMP-2 abundance. Future work will quantify changes in cell/sEV surface-bound TIMP-2 and MMP-2 alongside MMP-2 activation via flow cytometry and gelatin zymography respectively.
IMMU-20. INNATE IMMUNE EVASION IN MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Jeremy Vo, Juni S Mitra, Aaron Knox, Daniel Picard, Rajeev Vibhakar, Todd Hankinson, Siddhartha S Mitra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. Here, we report a cell surface proteome analysis of Group3-MB cell lines after direct MYC inhibition to identify changes in surface proteins and sensitivity to macrophage-mediated phagocytosis. METHODS We had previously demonstrated the preferential activity of HDACi (CI994) in MYC-driven medulloblastoma. CI-994, showed significant cell viability reduction mediated by reduction in the MYC (mRNA and protein), induction of apoptosis in MYC-driven medulloblastoma. In this study, we directly inhibited MYC using MYCi975 and OMO-MYC and carried out a cell surface proteomic analysis on Group3-MB cell lines to reveal CD24 and CD59 as potential immune evasion markers. While CD24 is a potential don’t eat me signal, CD59 is a ubiquitously expressed cell-surface glycosylphosphatidylinositol-anchored protein that acts as an inhibitor to the membrane attack complex and protects cells from CDC. In certain tumors, CD59 expression is enhanced, posing a significant obstacle to treatment by hindering effective monoclonal antibody-induced CDC. We use inhibitors to CD24 and CD59 to confirm their role as innate immune evasion proteins in Group 3MB. RESULTS Meta-analysis of published datasets reveals CD24 and CD59 as strong prognostic indicators in Group3-MB as well as within the Group3g-subtype. Inhibition of MYC reduces surface levels of CD24, increasing macrophage-mediated phagocytosis. The use of a blocking anti-CD24 mAb significantly enhanced macrophage-mediated phagocytosis. Furthermore, a significant reduction in surface expression was observed in CD59. Blocking CD59 mAb significantly enhanced anti-CD47 mAb mediated phagocytosis. Combined treatment of anti-CD24 and anti-CD47 significantly enhanced the survival of Grp3-MB tumor-bearing mice.
MDB-37. RAC1 INHIBITION FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: Nagi Ayad, Nitish Jangde
Journal: Neuro-Oncology (2024)

Abstract Despite considerable advances in identifying genetic and epigenetic abnormalities in medulloblastoma, many patients succumb to the disease. In addition, patients who respond to traditional therapy suffer from cognitive and intellectual deficits. Therefore, there is a dire need to identify novel therapies for treating medulloblastoma. Rho family GTPases are targets in multiple cancers including medulloblastoma. Rho, Rac1 and Cdc42 are essential mediators of cell-cell adhesion and cellular motility signaling, which are dysregulated in medulloblastoma. These GTPases are involved in the regulation of the cytoskeleton, cell migration, cellular proliferation, and developmental signaling. The small GTPase Rac1 has recently been reported as a possible therapeutic target in SHH-medulloblastoma due to its regulation of Hedgehog signaling via the GLI1 and GLI2 transcription factors. We have recently reported that GLI1/GLI2 are in a novel complex that contains the epigenetic regulators UHRF1 and DNMT1. Therefore, Rac1 may play a previously unappreciated role in epigenetic regulation of medulloblastoma by controlling the GLI1/GLI2/UHRF1/DNMT1 complex. To test this, we have utilized a novel brain penetrant Rac1 inhibitor termed GYS32661. GYS32661 treatment of medulloblastoma cells inhibits the GLI1-UHRF1 interaction. Importantly this inhibition of the interaction occurs rapidly suggesting that it is disrupting an early event in SHH signaling. GYS32661 also inhibits actin polymerization suggesting that utilizing this compound may provide a dual mechanism of inhibiting Shh signaling and cellular migration concurrently. GYS32661 is not toxic in animal models and is approximately 50% brain penetrant and therefore is an important clinical candidate for the treatment of medulloblastoma. Our studies identify an essential link between Rac1, Shh signaling, epigenetics, and cellular migration in medulloblastoma.
MDB-42. RADIOMIC TEXTURAL AND MORPHOLOGICAL-BASED FEATURES TO RISK-STRATIFY PEDIATRIC MEDULLOBLASTOMA PATIENTS
Authors: Marwa Ismail, Hyemin Um, Ralph Salloum, Peter de Blank, Pallavi Tiwari
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND One key determinate in the treatment pathway for pediatric medulloblastoma (MB), the most frequent malignant brain tumor in children, is accurate risk-stratification. MB tumors are classified as standard- or high-risk based on current approaches (Chang’s/molecular stratification). However, there is still a need for additional attributes towards reliable risk-stratification. This work presents a radiomic-based approach that combines textural- and morphological-based attributes to risk-stratify MB patients. Our rationale is that coupling texture and morphology attributes from the intra-tumoral regions that quantify the heterogeneity and disorderly nature of aggressive tumors can transcend the current clinical approaches in accurately stratifying tumors into high- and standard-risk. METHODS T1-weighted MRI scans of 119 MB patients (2–18 years) were collected from Cincinnati Children’s Hospital Medical Center (Site1-n=42), Children’s Hospital Los Angeles (Site2-n=47), and Children’s Hospital of Philadelphia (Site3-n=30), used interchangeably for training and testing. Following preprocessing and performing annotations for the enhancing lesion and edema sub-compartments, 232 textural and morphological features were extracted from each sub-compartment. Namely, 214 textural (gradient, Haralick, intensity, Gabor, Laws, entropy) as well as 34 morphological (4 surface-based (e.g., curvedness and sharpness), 18 global (e.g., roundness, elongation, compactness, flatness)) features were extracted. Features were then fed into Elastic-Net regression models for survival analysis. RESULTS Our analysis revealed that texture and morphology features, combined, yielded Concordance index (CI) and p-value of 0.52, 0.0001, respectively, for the enhancing lesion, using Sites1,3 for training, and CI=0.61, p=0.0065 using Site3 for testing. Additionally, for edema, CI and p-value of 0.514, 0.0001 were obtained when employing Sites2,3 for training and CI=0.61, p=0.00096 using Site1 for testing. Results were not significant when using Chang’s or molecular stratification alone for survival analysis. CONCLUSIONS Our study shows that radiomic-based morphological and textural features show promise towards reliable MB risk-stratification.