bluuebunny/crossref_metadata_2025_split huggingface dataset:
DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells
Authors: Monje Michelle , Majzner Robbie , Mahdi Jasia , Ramakrishna Sneha , Patel Shabnum , Chinnasamy Harshini , Yeom Kristen , Schultz Liora , Barsan Valentin , Richards Rebecca , Campen Cynthia , Reschke Agnes , Toland Angus Martin , Baggott Christina , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Jacobs Ashley , Yamabe-Kwong Karen , Rasmussen Lindsey , Nie Esther , Green Sean , Kunicki Michael , Fujimoto Michele , Ehlinger Zach , Reynolds Warren , Prabhu Snehit , Warren Katherine E , Cornell Tim , Partap Sonia , Fisher Paul , Grant Gerald , Vogel Hannes , Sahaf Bita , Davis Kara , Feldman Steven , Mackall Crystal 
Published: June 2022

Abstract
BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (&gt;95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.
DIPG-16. Evaluation of myeloid component of DIPG microenvironment
Authors: Mishra Deepak , Rajendran Sakthi , Zhu Xiaoting , Nazzaro Matthew , Kumar Shiva Senthil , Mchugh Todd , Rajappa Prajwal , Drissi Rachid 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable disease of the central nervous system in children with median overall survival of less than one year. In recent years, several immunotherapy strategies have emerged as an option to treat DIPG. However, the low mutational burden and rare infiltration of T lymphocytes, render these tumors immunologically “cold” and therefore pose challenges for general immunotherapy. The myeloid component was implicated in the immunosuppression in other solid tumors. Previous data have shown that DIPG tumors are enriched in macrophages, but their role in tumor growth and progression have not been elucidated. Specifically, it remains unclear whether the myeloid cells are recruited to the tumor microenvironment from the peripheral circulation. Here, we examined the recruitment of myeloid cell populations to the tumor microenvironment and further delineated their role in tumor progression in a syngeneic mouse model of DIPG. We showed that this DIPG mouse model displays an immune microenvironment similar to that of patients’ DIPGs. DIPG tumors harbored rare tumor infiltrating lymphocytes and are enriched in myeloid cells. To further characterize the phenotype and functions of these myeloid populations, we evaluated the changes in proportions of myeloid cell subsets using flow cytometry (CD11b, Ly6c, Ly6G, MHCII, F4/80, CD206, Arg1) in the bone marrow, peripheral blood, and in the tumor microenvironment during tumor progression. Also, we investigated the role of these myeloid cells in angiogenesis and immune suppression by performing histological and expression analyses of endothelial markers and chemokines (CD31, CD34, KDR, IL-10, IL-13, IL-4, CCL2, CCL5). Furthermore, decitabine (DNA methyltransferase inhibitor) treated tumors showed a decrease in myeloid population associated with a reduction in tumor growth, suggesting an important role of myeloid populations in tumor growth and progression.
DIPG-26. Targeted Protein Degradation of LSD1 synergizes with HDAC inhibitors in Diffuse Intrinsic Pontine Glioma
Authors: Groves Andrew , Poetschke Rebecca , Mire Hafsa , Panditharatna Eshini , Guzman Maria Tarazona , Qi Jun , Filbin Mariella 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) remains one of the most lethal brain tumors in all of childhood with no effective treatments besides radiation, which only extends survival a few months. Against this backdrop, our lab recently executed a focused CRISPR negative selection screen in DIPG cell lines after treatment with the histone deacetylase (HDAC) inhibitor panobinostat and discovered a strong co-dependence with the histone demethylase LSD1. To further explore the therapeutic potential of this synergistic interaction, we tested a drug library of HDAC- and LSD1- targeting drugs with the goal of identifying a combination with optimal synergy and blood brain barrier (BBB) penetration suitable for clinical translation. We were surprised to find that traditional catalytic LSD1 inhibitors had minimal effect in isolation and did not seem to synergize with HDAC inhibitors, while a recently described CoREST/LSD1 degrader named UM171 phenocopied the effects seen in our CRISPR screen. Degraders are a class of compounds that recruit an E3 ubiquitin ligase to a protein-of-interest and cause target ubiquitination and proteasomal degradation. Given our unexpected finding, we hypothesized that UM171 induces synergy with HDAC inhibitors through elimination of a scaffolding function of LSD1. To prove this, we knocked out LSD1 using CRISPR/Cas9 and subsequently treated with a panel of HDAC inhibitors, which showed a signification sensitization of DIPG cells to HDAC inhibitors compared to standard controls. We also confirmed that UM171 interacts with the CoREST complex (members include LSD1, RCOR1, HDAC1/2) by performing streptavidin bead pull down with a newly synthesized biotin-conjugated UM171 probe. In summary, our results show that targeting LSD1 for degradation in combination with HDAC inhibition is a synergistic strategy in DIPG worthy of further translational study.
DIPG-36. The brain-gut-microbiota axis to predict outcome in pediatric diffuse intrinsic pontine glioma
Authors: De Cecco Loris , Biassoni Veronica , Schiavello Elisabetta , Carenzo Andrea , Iannò Maria Federica , Licata Armando , Marra Manuela , Carollo Maria , Boschetti Luna , Massimino Maura 
Published: June 2022

Abstract
OBJECTIVE: Diffuse intrinsic pontine glioma (DIPG) is a rare childhood brain tumour with poor prognosis. Radiotherapy (RT) remains the only palliative intervention. In this scenario, it is essential to investigate tumor and patient microinvironment. Microbiota plays a critical role in human health and a functional link between the central nervous system and gut microbiota has been reported: the microbiota-gut-brain axis. With these premises, we have investigated the gut microbiota in DIPG. METHODS: A cohort of 18 patients was enrolled and we collected stool specimens at diagnosis (pre-RT) and after radiotherapy. Microbiota content was analysed through 16S rRNA sequencing on IONS5xl; base calling and demultiplexing were performed by Torrent Suite (ThermoFisher). Association to progression free survival (PFS) and overall survival (OS) were assessed by cox-regression univariate analyses and differential abundance (DA) analyses identified differences following RT. RESULTS: The Firmicutes/Bacteroidetes (F/B) ratio in pre-RT specimens has a median of 0.757 (range= 0.243-1.19). Having PFS as endpoint and at family classification level, an increased risk of disease progression was disclosed for Flavobacteriaceae and Bacillales with HR of 1.57 (p=0.00913) and 1.57 (p=0.215), respectively. The anaerobic bacteria Synergistaceae is found related to a decreased risk of progression with HR 0.662 (p=0.00718). These findings were also confirmed with OS as endpoint. DA analyses pointed out a number of families belonging to Firmicutes and Bacteroidetes phyla highly differentiated (log2|fold-change|&gt;2) between pre- and post-RT. CONCLUSIONS: This study represents the first report of the microbiota-gut-brain axis role in DIPG patients. The F/B ratio, a parameter of normal intestinal homeostasis, show the presence of inflammatory patterns and some family members are associated to increased disease progression. These preliminary findings needs further validations. However, 16S microbiota has the potential ability to stratify patients and probiotic administration could restore a normal F/B ratio.
DIPG-44. H3K27-altered diffuse midline gliomas with secondary driver molecular alterations
Authors: Gestrich Catherine , Grieco Kristina , Lidov Hart , Ligon Keith , Santagata Sandro , Yeo Kee Kiat , Alexandrescu Sanda , Meredith David 
Published: June 2022

Abstract
INTRODUCTION: Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-altered, but their significance is not completely explored. We evaluated these associations in our institutional cohorts. MATERIALS AND METHODS: We searched our sequencing data base (2013-2020) for H3K27M-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Copy number profiles were evaluated using BioDiscovery's Nexus Copy Number software package. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. RESULTS: We identified 77 patients (age range 2-68, median 26). The diagnosis was DMG (n=55), anaplastic astrocytoma/glioblastoma (n=19), low-grade glioma (n=1), low-grade glioneuronal tumor (n=1), and ganglioglioma (n=1). Recurrent alterations were seen in TP53 (n=42), ATRX (n=17), NF1 (n=15), PDGFRA (n = 4). Five cases had BRAF V600E (1 ganglioglioma; 4 DMG); twelve had FGFR1 mutations (9 DMG; 3 anaplastic astrocytoma/glioblastoma). The most common location in the BRAF group was the brainstem and in the FGFR1 was the thalamus. Survival ranged from 0 to 97 months, median 12.9 months (28.8 months for FGFR1 and 22.8 for the BRAF V600E). This was not significantly different from OS reported in the literature for DMG.The BRAF V600E ganglioglioma patient is alive 37 months after diagnosis. CONCLUSION: There was no significant difference in outcomes for patients with secondary molecular drivers when compared with conventional H3K27M DMG. The outcome of the BRAF V600E tumors seemed to correlate with the histology. These findings and the possibility of targeted therapy argue for comprehensive sequencing of H3K27-altered gliomas.
DIPG-52. Activators of the integrated stress response synergize to kill DIPG
Authors: Novak Orlandi , Arnold Antje , Eberhart Charles , Raabe Eric 
Published: June 2022

Abstract
DIPG has elevated baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that allows cells to tolerate various forms of stress. Increased expression of activating transcription factor 4 (ATF4) indicates activation of the ISR. Intermediate levels of ATF4 protect cells from stress, while sustained high levels result in cell death. The imipridone drug ONC201 binds to and activates the mitochondrial protease ClpP, leading to increased mitochondrial stress and persistent ATF4 activation. Because DIPG has a high baseline level of ATF4, we hypothesized that the ISR activators Sal003, ONC201, and fenretinide would synergize to kill DIPG. Sal003 inhibits dephosphorylation of ATF4 upstream regulator, eIF2α. The retinoic acid derivative fenretinide induces ATF4, increases reactive oxygen species, and has clinical activity in pediatric patients with neuroblastoma. After determining the IC25 of Sal003, fenretinide, and ONC201, we treated patient-derived DIPG cell lines with low micromolar doses. The combination of Sal003 and ONC201 significantly increased apoptosis as measured by CC3 immunofluorescence in comparison to DMSO (p&lt;0.0001, ANOVA). Combination therapy also significantly increased CC3 positivity compared to single treatment. Western blots for cleaved PARP expression detected induction of apoptosis in DIPG treated with both Sal003 and ONC201 over DMSO and monotherapy treated cells. In some cell lines, the combination increased ATF4 expression. Since Sal003 is not yet available for clinical testing in humans, we treated DIPG cells with ONC201 and fenretinide. CC3 immunofluorescence indicated synergistically elevated apoptosis in the combination of ONC201 and fenretinide vs. DMSO (p&lt;0.0001, ANOVA). Western blots showed increased cleaved PARP, ATF4, and CHOP expression in DIPG treated with ONC201 and fenretinide. We are currently testing the efficacy of this combination in orthotopic DIPG xenografts. Our results suggest the combination of ONC201 with fenretinide could potentially serve as a therapy for DIPG.
DIPG-59. Blood Brain Barrier (BBB) modulation using Cadherin peptides in the treatment of Diffuse Midline Glioma of the Pons (DMG-P)
Authors: Line Stacey , Sajesh Babu Velayuthan , Schwinghamer Kelly , Yathindranath Vinith , Tsoli Maria , Ziegler David , Siahaan Teruna , Miller Donald , Vanan Magimairajan Issai 
Published: June 2022

Abstract
BACKGROUND: Diffuse midline glioma of the Pons (DMG-P) is the most common brainstem tumor of childhood and is universally fatal. The BBB is frequently intact in DIPG and restricts entry of systemically administered conventional and biological therapies. We have synthesized and validated synthetic cadherin peptides (HAV6, HAVN1) that cause transient opening of the BBB by preventing the dimerization of the extracellular membrane bound VE-Cadherin in the vascular endothelium. METHODS: We used DMG-P tumor conditioned media (TCM) and co-cultures in two in-vitro model systems (trans well inserts, Blood Brain Tumor Barrier microfluidics model (BBTB-DMG-P microchip)-using Human Brain microvascular endothelial cells (HBMVECs) / SF8628 (DMG-P PDX) and validated the in-vitro findings in a DMG-P orthotopic murine model using RA055. The permeability of different molecular weight markers [(Gd-DTPA, IRDye 800CW PEG, rhodamine 800 (R800)] were examined in presence / absence of HAV6 / HAVN1 peptides. RESULTS: The BBTB integrity is maintained in-vitro as evidenced by decreased permeability of all the agents across the barriers in the TCM / co-culture models. Addition of HAV6/ HAVN1 peptides in-vitro increased the permeability of all the agents across the barriers. The permeability of R800 increased in the presence of Elacridar (P-gp inhibitor). The BBB was intact in the DMG-P murine model, as evidenced by minimal Gd-DTPA contrast enhancement in T1 weighted MRI images. Administration of HAV6 / HAVN1 peptides resulted in Gd-DTPA contrast enhancement of the tumor at 5- and 10-minutes post injection. CONCLUSION: Our data confirms that the BBTB is intact in DMG-P and can be transiently modulated using synthetic cadherin peptides. Transient BBTB opening using synthetic peptides will help BBB non-penetrant chemotherapy drugs like Vincristine/Mitoxantrone and biological therapies to reach intra-tumoral therapeutic levels and improve therapeutic efficacy.
DDEL-05. Intraventricular therapy with topotecan is feasible and safe: Experience in 50 pediatric patients with various malignant brain tumors
Authors: Peyrl Andreas , Stepien Natalia , Mayr Lisa , Azizi Amedeo , Gojo Johannes , Baumgartner Alicia , Hedrich Cora , Lippolis Maria Aliotti , Slavc Irene 
Published: June 2022

Abstract
BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (&gt;1 and &lt;2 years 0.25mg, &gt;2 and &lt;3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.
EPCT-01. Pediatric Brain Tumor Consortium (PBTC)-055: A phase I study of trametinib and hydroxychloroquine (HCQ) for BRAF-fusion or Neurofibromatosis type-1 (NF1)-associated pediatric gliomas
Authors: Hoffman Lindsey M , Levy Jean Mulcahy , Kilburn Lindsay , Billups Catherine , Stokes Vanetria , McCourt Emily , Poussaint Tina Young , Campagne Olivia , Partap Sonia , Dorris Kathleen , Sait Sameer Farouk , Robinson Giles , Baxter Patricia , Stewart Clinton F , Fangusaro Jason , Onar-Thomas Arzu , Dunkel Ira 
Published: June 2022

Abstract
INTRODUCTION: Autophagy is a highly conserved process by which intracellular components are degraded and recycled promoting cell survival. Preclinically, autophagy has been implicated as a resistance mechanism in BRAF-mutant glioma cells treated with MAPK-pathway inhibitors. HCQ, an oral autophagy inhibitor, has been evaluated preclinically and clinically to overcome resistance. METHODS: PBTC-055 (NCT04201457) is a phase I/II trial of HCQ combined with trametinib (BRAF-fusion or NF1-associated gliomas) or trametinib and dabrafenib (BRAFV600E gliomas) in patients &lt; 30 years with progressive glioma. Prior treatment with RAF and/or MEK inhibitor with sub-optimal response (no response or response followed by progression on therapy) was required. Here, we present phase I data combining trametinib with HCQ utilizing a rolling-6 design. HCQ was administered at escalating dose levels (8, 15, or 20 mg/kg/day divided BID) in combination with standard pediatric trametinib dosing. All patients received prior MEK inhibitor therapy; 5/18 (28%) exhibited no response and 13/18 (72%) progressed on active therapy. RESULTS: Eighteen eligible/evaluable subjects were enrolled. Median age was 9.6 years (2.5-20.4 years); 10 were male. There were 2 dose-limiting toxicities (both grade 3 rash one each at DL1 and DL3). The highest dose level of HCQ (20 mg/kg/day divided BID) was declared the RP2D. Grade 3 adverse events possibly related to therapy included skin infection, rash, cardiac ejection fraction decrease, weight loss, and anorexia. There were no grade 4 or 5 attributable toxicities. Preliminarily, combination pharmacokinetic assessment revealed similar metabolism of trametinib to that reported as a single agent; HCQ demonstrated more rapid clearance compared to adults. Pharmacodynamic assessments are ongoing. CONCLUSIONS: The combination of trametinib and HCQ is safe with a RP2D of HCQ of 20 mg/kg/day divided BID. Currently, subjects are enrolling on the phase II portion evaluating the efficacy of this novel combination.
EPCT-03. Working together to accelerate the preclinical to clinical translation of drug delivery systems for children’s brain tumours
Authors: Campbell Emma , Aquilina Kristian , Dandapani Madhumita , Walker David , Rahman Ruman 
Published: June 2022

Abstract
Children's brain tumours are the biggest cancer killer in children and young adults. Several techniques, such as intra-cerebrospinal fluid chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems, electric field therapy, and intra-arterial and intra-nasal chemotherapy, have the potential to transform the treatment of brain tumours in children. However, there have been very few clinical trials to evaluate these. In 2021, the CBTDDC (Children’s Brain Tumour Drug Delivery Consortium) and the ITCC (Innovative Therapies for Children with Cancer) brain tumour group established a Clinical Trials Working Group comprising international researchers and clinicians to address this issue. This partnership highlighted the main challenges in preclinical to clinical translation of paediatric CNS drug delivery as: (1) a lack of specific funding for prototype development and/or scale-up for clinical trials; (2) difficulties in navigating the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multi-centric working. In response to this, we ran a hybrid workshop in November 2021 on ‘Clinical Trial Readiness for CNS Drug Delivery’. At this workshop, around 50 delegates (comprising clinicians, researchers, trial regulatory experts, policy makers, and representatives from funding organisations, brain tumour charities and industry) came together to discuss issues around funding, preclinical models and regulatory processes. We have established speciality-specific working groups to build on the workshop discussions, with the aim of producing recommendations around the use of preclinical models and drug delivery techniques according to brain tumour type. We have also used the workshop presentations and discussions to create a ‘Roadmap’ document for preclinical to clinical translation, which will be freely shared with the neuro-oncology research community. We continue to liaise with funders and regulatory bodies to address the changes that are needed in these areas. If you would like to join our network, contact: cbtddc@nottingham.ac.uk