bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMMU-08. Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: efficacy, safety, biomarker, and pharmacokinetic results from Checkmate 908
Authors: Dunkel Ira J , Cohen Kenneth , Foreman Nicholas K , Hargrave Darren , Lassaletta Alvaro , André Nicolas , Hansford Jordan R , Hassall Tim , Eyrich Matthias , Gururangan Sridharan , Bartels Ute , Gajjar Amar , Howell Lisa , Warad Deepti , Pacius Misena , Tam Rachel , Wang Yu , Zhu Li , Doz François 
Published: June 2022

Abstract
BACKGROUND: Limited data exist regarding checkpoint inhibitor efficacy for pediatric CNS malignancies. METHODS: CheckMate 908 is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in 5 cohorts of pediatric patients previously treated with standard-of-care (NCT03130959). Patients received NIVO-3mg/kg Q2W or NIVO-3mg/kg + IPI-1mg/kg Q3W (4 doses) followed by NIVO-3mg/kg Q2W. Primary endpoints included OS (newly diagnosed DIPG) and PFS (other CNS cohorts); secondary endpoints included other efficacy metrics/safety. Exploratory endpoints included pharmacokinetics/biomarker analyses. Comparisons between treatments/cohorts were not planned. RESULTS: At data cutoff (13-Jan-2021), 166 patients received NIVO (n=85) or NIVO+IPI (n=81) at median (m) ages of 10.0yrs (range, 1-21) and 11.0yrs (1-21), respectively. In newly diagnosed DIPG, mOS (80% CI) was 11.7mos (10.3-16.5) with NIVO (n=23) and 10.8mos (9.1-15.8) with NIVO+IPI (n=22). In recurrent/progressive HGG, mPFS (80% CI) was 1.7mos (1.4-2.7) with NIVO (n=16) and 1.3mos (1.2-1.5) with NIVO+IPI (n=15). In relapsed/resistant medulloblastoma, mPFS (80% CI) was 1.4mos (1.2-1.4) with NIVO (n=15) and 2.8mos (1.5-4.5) with NIVO+IPI (n=15). In relapsed/resistant ependymoma, mPFS (80% CI) was 1.4mos (1.4-2.6) with NIVO (n=12) and 4.6mos (1.4-5.4) with NIVO+IPI (n=10). In other recurrent/progressive CNS tumors, mPFS (95% CI) was 1.2mos (1.1-1.3) with NIVO (n=19) and 1.6mos (1.3-3.5) with NIVO+IPI (n=19). Median treatment duration was 2.1mos (range, 0-41.7+ [NIVO]/0-29.6+ [NIVO+IPI]). Grade 3/4 treatment-related AEs occurred in 14.1% (NIVO) and 27.2% (NIVO+IPI) of patients. NIVO and IPI first dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor PD-L1 expression was not associated with survival. Tumor mutational burden was high in 1 patient (NIVO+IPI) with HGG (OS=11.0mos). CONCLUSIONS: NIVO±IPI demonstrated no clinical benefit in pediatric patients with high-grade CNS malignancies, consistent with available historical data. The safety profiles were manageable.
IMMU-19. Outcomes of Pediatric Patients with High-Risk CNS Tumors Treated with Multi-tumor associated antigen specific T cell (TAA-T) therapy: the ReMIND trial
Authors: Hwang Eugene , Fortiz Fernanda , Cruz Russell , Geiger Ashley , Grant Melanie , Lang Haili , Shibli Abeer , Burnett Sianna , Lazarski Chris , Tanna Jay , McCann Chase , Hoq Fahmida , Hanley Patrick , Kilburn Lindsay , Rood Brian , Packer Roger , Bollard Catherine 
Published: June 2022

Abstract
BACKGROUND: The ReMIND trial hypothesizes that autologous T-cells specific for three tumor-associated antigens (TAA) -WT1, PRAME, and survivin- will be safe and elicit anti-tumor immunity in pediatric patients with CNS cancer. METHODS: Patients (n=25) received autologous TAA-T for newly-diagnosed DIPG (Stratum A, up to 4x107/m2) or recurrent CNS malignancies (Stratum B, up to 8x107/m2) in this dose-escalation study (NCT03652545) and were monitored for toxicity and response. RESULTS: Autologous TAAT products were successfully manufactured from 28 patients. Using IFN-γ ELISPOT assay, 10/11 evaluable products had specificity for 1-3 TAAs. 25 patients received TAA-T (6 in Stratum A and 19 in Stratum B) and completed the 45-day safety monitoring period. Twenty-four (96%) had no dose limiting toxicities (DLT), but 1 (4%) patient with DIPG experienced a DLT related to potential immune-mediated pseudoprogression. Median overall survival for patients with DIPG (Stratum A) was 14 months (range, 6-32 months). Median progression-free survival (PFS) for Stratum B patients was 8 months (range, 2-26+ months), which exceeded their preceding median duration of disease stability of 2 months (range, 1-5 months). Plasma cytokine profiles demonstrated infusion-related immune cytokine responses. CONCLUSIONS: In summary, TAAT had a favorable toxicity profile (4%) especially compared to CAR-T therapy and may elicit anti-tumor immune responses that contribute to prolonged survival. Immunobiology studies and response assessments are ongoing for both strata. Based on these encouraging preliminary results, we have added a stratum that includes prescribed lymphodepletion pre TAA-T administration at a cell dose of 8x107/m2. Further, we plan to add an additional stratum to allow direct administration of TAA-T into the CNS via an Ommaya reservoir.
IMMU-21. Targeting the adenosinergic immune suppression pathway in high grade glioma synergizes with innate immune checkpoint blockade
Authors: Liu Yifan , Chetty Senthil Lakshmana , Cole Allison , Cruz Joselyn Cruz , Hoffmeyer Eric , Vibhakar Rajeev , Venkataraman Sujatha , Mitra Siddhartha 
Published: June 2022

Abstract
Immune response in the tumor microenvironment is modulated by the conversion of eATP to AMP to adenosine via the ecto-enzymes CD39 and CD73. Overexpression of CD73 in tumors leads to an increase in extracellular adenosine concentration and decrease in eATP, resulting in immune suppression. In this study, CD73 knockouts were created in adult and pediatric glioma cell lines (DIPG17, T3691, BT245) and used to quantify the effects of CD73 knockout on macrophage phagocytosis in the presence of extracellular AMP. In cell line DIPG17, CD73 knockout significantly increased phagocytosis with and without external AMP compared to the WT. In the WT condition, addition of AMP significantly reduced phagocytosis, while this decrease was not significant in the CD73-KO. The addition of anti-CD47 antibody significantly increased phagocytosis with external AMP in the WT condition. Similar results were obtained with cell line T3691. However, CD73 knockout combined with anti-CD47 treatment and external AMP showed significantly greater phagocytosis than the WT condition. This suggests that a combination of anti-CD73 and anti-CD47 treatment may be more effective in the tumor microenvironment. Lastly, in cell line BT245, CD73 knockout significantly increased phagocytosis as seen in the other cell lines. However, no significant difference was observed between WT and CD73-KO with extracellular AMP or anti-CD47. In vivo studies were conducted in orthotopic xenograft mouse models with DIPG17 CD73 knockout cells. Combination treatment with anti-CD47 antibody significantly decreased tumor burden and prolonged survival in the CD73-KO tumors compared to anti-CD47 treated DIPG13-WT tumors. We conclude that the CD73 adenosinergic pathway and the CD47-SIRPα pathway may present a target for immunotherapy in pediatric and adult gliomas.
IMMU-22. Safely targeting GD2 in thalamic diffuse midline glioma with mRNA CAR T cells
Authors: Foster Jessica , Griffin Crystal , Stern Allison , Madsen Peter , Storm Phillip , Resnick Adam 
Published: June 2022

Abstract
Chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 have shown promise as a therapeutic for diffuse midline glioma (DMG). However, prior studies raised significant concerns of neurotoxicity and fatality when using virally transduced CAR T cells against midline thalamic tumors. Building upon our prior work optimizing mRNA for use in CAR T cells (Hum Gen Ther, 2019), we hypothesized repeated dosing of transient GD2-directed mRNA CAR T cells could be employed for safe and effective treatment of thalamic DMG. GD2-directed CAR T cells were created using mRNA encoding the 14G2a single chain variable fragment paired with 41BB and CD3-zeta co-stimulatory domains and transfected into human T cells. CAR T cells were tested against the murine thalamic DMG xenograft 7316-6349 via locoregional delivery with an indwelling infusion catheter for repeated dosing. The previously reported fatal neurotoxicity observed in mice using lentiviral CAR T cells could be recapitulated with aggressive dosing. Four doses of 5 x 106 mRNA CAR T cells delivered intratumorally twice a week resulted in median overall survival of 9 days for GD2-treated mice compared to &gt;30 days for CD19-treated controls (p&lt;0.01). This toxicity could be avoided by decreasing the dose and timing of infusions to 2 x 106 mRNA CAR T cells delivered once weekly. Bioluminescent imaging showed regression of tumor in GD2-treated mice compared to CD19-treated controls (radiance fold change -3 x106 versus +20x106 p/sec/cm2/sr, p&lt;0.01). Notably, non-tumor bearing mice treated with GD2-directed CAR T cells quickly developed fatal neurotoxicity within 14 days, suggesting on-target/off-tumor effect of the CAR T cells and a very narrow therapeutic window in the brain. These data highlight the utility of titratable mRNA-based CAR T cell therapy for CNS tumors and establish GD2-directed mRNA CAR T cells as a safe and effective method for treating thalamic DMG.
LGG-09. A Nationwide Service Evaluation of Safety, Radiologic and Visual Outcome Refining Bevacizumab-based Treatments in Children with Progressive Low-Grade Glioma
Authors: Green Katherine , Panagopoulou Paraskevi , D’Arco Felice , O'Hare Patricia , Bowman Richard , Walters Bronwen , Dahl Christine , Jorgensen Mette , Patel Pritesh , Slater Olga , Ahmed Rehana , Bailey Simon , Carceller Fernando , Collins Rhiannon , Corley Elizabeth , English Martin , Hayden James , Howells Lisa , Kamal Ahmed , Kilday John Paul , Lowis Stephen , Lumb Blanche , Micic Thomas , Mitra Dip , Pace Erika , Picton Susan , Pizer Barry , Shafiq Ayad , Uzunova Lena , Wilson Shaun , Wayman Harriet , Hargrave Darren , Opocher Enrico 
Published: June 2022

Abstract
INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort.
METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed.
RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), &gt; 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS.
CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual &gt; radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.
LGG-11. Analysis of neurosurgical complications in pediatric supratentorial midline low-grade glioma – results from the German LGG studies
Authors: Weiß Sarah , Schulz Matthias , Kandels Daniela , Driever Pablo Hernáiz , Witt Olaf , Thomale Ulrich-Wilhelm , Gnekow Astrid , le Simon Michè 
Published: June 2022

Abstract
OBJECTIVE: Around 80% of all pediatric low-grade glioma (LGG) patients undergo at least one tumor surgery. Interventions in the supratentorial midline (SML) are particularly challenging due to the proximity of eloquent areas, yet associated complications are scarcely reported. We investigated the frequency of neurosurgical complications and related impairments and aimed at identifying risk factors for their appearance related to patient characteristics or the procedure. PATIENTS AND METHOD: Records were retrospectively analyzed from 321 patients with SML-LGG from the successive multicenter German LGG studies, who underwent neurosurgery at 63 hospitals between May 12th,1998 and June 27th, 2020. RESULTS: 543 operations (235 resections, 168 biopsies, 140 non-tumor interventions) were performed on 321 patients (54% male, median age 9 years, 11% NF1 positive, 43% visual pathway glioma). Surgical mortality rate was 0,93% (n=3). Applying the Drake classification postoperative surgical morbidity was observed in 259 cases (47,7%), medical morbidity in 103 cases (19%). 30-day persistence rate of newly developed neurological deficits was 44,8% (65/165 cases); neuroendocrine impairment affected 57 patients (17,8%), visual deterioration 34 (10,6%). Complications/impairments following resections were associated with patient age below 3 years at operation, tumor volume above 80 cm3, presence of hydrocephalus prior to surgery, complete resection, intervention in centers with fewer reported resections and surgery performed between 1998-2006 by univariate analysis. In contrast, the neurosurgical approach, tumor location, NF1 status as well as previous antineoplastic treatment were not associated with the frequency of complications. Regarding biopsies, open biopsies showed significantly more surgery-associated complications/impairments compared with stereotactic procedures. CONCLUSIONS: Neurosurgery-associated complications and impairments were frequent in pediatric patients with supratentorial midline LGG undergoing open surgery in the German LGG-studies. We identified six patient- and institution-associated factors that may increase the risk for surgical complications. Skills at the treating center and extent of resection should be considered appropriately prior to intervention.
LGG-27. Molecular implications of mitogen-activated protein kinase pathway inhibition by the MEK inhibitor trametinib in BRAF-fusion-driven pediatric pilocytic astrocytoma
Authors: Sigaud Romain , Stefanski Anja , Selt Florian , Hielscher Thomas , Usta Diren , Kocher Daniela , Picard Daniel , Büdenbender Isabel , Remke Marc , Pfister Stefan M , Jones David T W , Brummer Tilman , Witt Olaf , Milde Till 
Published: June 2022

Abstract
Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by driving alterations in the mitogen-activated protein kinase (MAPK) pathway, leading to its constitutive activation and modulating the balance between cell proliferation and oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA susceptible to MAPK inhibitor (MAPKi) therapies, which show encouraging results in phase 1/2 clinical trials. However, little is known about the molecular implications of MAPK inhibition in PA. The DKFZ-BT66 cell line, derived from a primary KIAA:BRAF-fusion positive PA, was used as a model system. DKFZ-BT66 were treated with the MEKi trametinib for different durations in both proliferative and senescent states. Gene expression was analyzed by gene expression profiling and protein expression/phospho-regulation by data-dependent mass spectrometry followed by label-free quantitative analysis. A time course analysis based on differentially expressed genes and phosphorylated proteins was performed, followed by a single-sample gene set enrichment analysis (ssGSEA) and kinase substrate enrichment analysis, respectively. Differential gene expression analysis revealed that MEK inhibition led to the inhibition of the OIS/SASP gene programs in senescent DKFZ-BT66, with downregulation of key OIS/SASP partners such as IL1B on the protein level. This functionally translated into a de-sensitization of these cells towards the senolytic agent navitoclax. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. This data indicates that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help increase treatment’s efficacy. Validation of these targets by post-translational modification enrichment analysis of the phospho-proteomics dataset is ongoing.
LGG-41. The clinical and molecular landscape of gliomas in adolescents and young adults
Authors: Bennett Julie , Nobre Liana , Sheth Javal , Ryall Scott , Fang Karen , Johnson Monique , Negm Logine , Chung Jiil , Komosa Martin , Nunes Nuno M , Fat Mary Jane Lim , Perry James , Sahgal Arjun , Detsky Jay , Bouffet Eric , Naz-Hazrati Lili , Dirks Peter , Ertl-Wagner Birgit , Kongkham Paul , Zadeh Gelareh , Mason Warren , Climans Seth , Cusimano Michael , Das Sunit , Gao Andrew , Tsang Derek , Nguyen Lananh , Laperriere Normand , Keith Julia , Munoz David , Tabori Uri , Hawkins Cynthia 
Published: June 2022

Abstract
OBJECTIVE: Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach based on data from adults. The clinical impact of paediatric-type alterations in these tumours is unknown. METHODS: We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Complete molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS: A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH-mutant tumours account for only 53%, while paediatric-type mutations were found in 35% of AYA tumours with IDH-WT GBM accounting for the remaining 12%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (6%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients &gt;20 years suggesting malignant transformation possibly due to higher rate of secondary hits including TP53, CDKN2A and ATRX mutations. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS: Gliomas in AYA are enriched for paediatric-type alterations with distinct molecularly-based outcomes. As these tumours carry different outcomes than childhood glioma and may respond to targeted inhibitors, AYA gliomas would benefit from comprehensive diagnostic and therapeutic approaches.
LGG-44. Multi-omic analysis reveals integrated signalling networks in paediatric low-grade glioma
Authors: Woodward Lewis , Jones Tania A , Patel Ankit , Dokal Arran D , Stone Thomas J , Rajeeve Vinothini , Cutillas Pedro R , Jones David T W , Hargrave Darren , Jacques Thomas S , Sheer Denise 
Published: June 2022

Abstract
Paediatric low-grade gliomas (pLGGs) are the most common type of childhood CNS tumours. Our study included pilocytic astrocytomas (PAs; KIAA1549:BRAF), glioneuronal tumours (GNTs; BRAFV600E) and location-matched controls. We initially performed kinase substrate enrichment analysis (KSEA) to infer differential kinase activity, which allowed us to identify altered signalling networks in the two tumour types. Here we report the integration of these kinase signalling networks together with total proteomics, transcription factor enrichment analysis (TFEA) and transcriptomics (coding and non-coding). Total proteomic profiling confirmed an increase in proteins involved in cell cycle, inflammatory response and signal transduction in PAs, whilst there was an increase in proteins promoting cell growth, immune response and inflammation in GNTs. TFEA was performed using the DoRothEA database to identify master transcriptional regulators. We observed signiﬁcant activation of transcription factors (TFs) that are direct targets of MAPK signalling in both tumour types. Notable differences include the higher activation of NF-kB/STAT TFs in PAs and the increased activation of RFX1/2 in GNTs. Next, we constructed kinase-TF networks and identified multiple kinases targeting STAT3 in PAs and STAT1/3 in GNTs. Pathway analysis of RNA-Sequencing data showed enrichment of NF-kB in both tumours and repression of E2F target genes (PA) and reduced expression of MYC target genes (GNT). We developed a BRAF-OIS signature and found 23 genes commonly enriched in both tumour types, highlighting shared senescence-associated targets. MicroRNA profiling identified upregulation of microRNAs that target MAPK and NF-kB signalling networks, and many down-regulated microRNAs with tumour suppressive roles. Finally, we identified several lncRNAs known to be differentially expressed in glioma and, whilst their mechanism(s) of action are varied, they are thought to act with other well-established regulators to fine-tune cellular processes. Taken together, we present a comprehensive signalling network as a framework for studying pLGGs.