bluuebunny/crossref_metadata_2025 huggingface dataset:
DIPG-92. IMMUNE ACTIVATION STUDIES WITH THE NEOANTIGEN-BASED PEPTIDE VACCINE RHSC-DIPGVAX DEMONSTRATE ANTIBODY-MEDIATED RESPONSES AND EPITOPE SPREADING IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: Sipila Patrick , Boland Lauren , Miska Jason M , Chi Susan N , Sato Mariko , Plant-Fox Ashley S , Narendran Aru
Published: June 2024

BACKGROUND

Approximately 80% of DIPGs carry gain-of-function lysine-to-methionine (K27M) mutations in histone H3 proteins that frequently co-occur with other protein aberrations, including p53, ACVR1, and PDGFRA. Because the DIPG microenvironment has few infiltrating immune cells, resolution of negative regulatory mechanisms through checkpoint blockade may be necessary to promote vaccine-induced anti-tumor responses. Accordingly, rHSC-DIPGVax is a neoantigen-based peptide vaccine combined with checkpoint inhibitors currently under investigation in clinical trial, NCT04943848. The vaccine contains 16 neoantigen peptides, QS-21 adjuvant, and recombinant heat shock protein, Hsc70. In this study, we investigate vaccine-induced antibody-mediated immunity and the phenomenon of epitope spreading, an extension of the immune response to secondary epitopes not directly targeted by the therapy, thus promoting distinct, individualized responses.

METHODS

rHSC-DIPGVax is administered every two weeks to patients with DIPG and blood is collected pre-treatment and prior to each dose. To investigate vaccine-induced immunoreactivity to neoantigens targeted by rHSC-DIPGVax, DIPG lysates resolved by two-dimensional gel electrophoresis are immunoblotted with pre- and post-vaccine patient plasma containing antibodies against vaccine antigens. Proteins are immunoprecipitated (IP) from DIPG lysates, followed by mass spectrometry (MS) identification and validation.

RESULTS

In eight subjects to date, vaccination with rHSC-DIPGVax consistently induces IgM and IgG antibodies against proteins directly targeted by the vaccine, including strong immunoreactivity to ACVR1. Furthermore, antibodies against several secondary proteins are also detected in post-vaccination plasma. Immunoblotting and IP-MS analysis identified several distinct candidates of epitope spreading, including the tumor antigens CEP290, DNAH3, HRNR, KDM6B, LAMA5, and TRPA1.

CONCLUSIONS

rHSC-DIPGVax induces antibody-mediated tumor-specific responses to DIPG neoantigens, including direct vaccine targets and secondary targets via intra- and inter-molecular epitope spreading. We also present an experimental protocol to investigate vaccine-induced immune activation. Our ongoing studies aim to validate epitope spreading candidates and determine the important biological correlates between antibody responses and clinical outcomes.
DEI-01. CLINICAL AND SOCIOECONOMIC FACTORS ASSOCIATED WITH PARTICIPATION IN POST-MORTEM TISSUE DONATION IN PEDIATRIC BRAIN TUMORS: A RETROSPECTIVE CHART REVIEW
Authors: Boland Lauren K , Kabat Judith M , Williams Melissa , Lenzen Alicia , Plant-Fox Ashley S , Wadhwani Nitin , Waanders Angela J
Published: June 2024

BACKGROUND

The gift of post-mortem tissue donation is a critical resource in the discovery and interrogation of pathobiological mechanisms of pediatric brain tumors. Broad generalizability of research findings requires a representative population to participate in pre-clinical studies. As a “Center of Excellence” within the Gift from a Child initiative, our institution has a well-established post-mortem tissue donation program funded by the Swifty Foundation. Our primary objective was to determine if clinical and socioeconomic differences exist between patients that participated in and those that declined research-based autopsy.

METHODS

We performed a single-institution retrospective chart review of pediatric patients with central nervous system (CNS) malignancies who died from their disease between 1/1/2021 and 12/31/2022. Individual clinical, demographic, and socioeconomic data were assessed. Population-level data were estimated using Zip Code Tabulation Areas. Descriptive statistics were used to compare categorical data.

RESULTS

Among 26 patients who died secondary to disease in the study timeframe, 23 (88%) were approached and 8/23 (35%) consented to participation. In the consented group (C) vs. declined group (D), there was a higher percentage of White, Non-Hispanic/Latino patients by self-reported race (C: 88% vs. D: 55%) and no patients who identified as Asian or Hispanic/Latino (C: 0% & 0% vs. D: 13% & 27%). Of all patients approached, 2 required interpreters (9%) and both families declined participation. The rate of private insurance was higher in the consented group (C: 75% vs D: 47%) compared to Medicaid as primary insurance in the declined group (C: 13% vs D: 53%).

CONCLUSIONS

Patients from racial and ethnic minorities are underrepresented in tissue donation programs. Future research should aim to understand and improve identified disparities to ensure advancements benefit all children with CNS malignancies. One area we plan to address is improved communication with non-English speaking families by educating interpreter services prior to discussion.
DEI-02. DIRECT PATIENT OUTREACH IN PEDIATRIC NEURO-ONCOLOGY TO IMPROVE ACCESS TO GENOMIC PROFILING – THE MAKE-AN-IMPACT PROGRAM
Authors: Sait Sameer Farouk , O’Donohue Tara , Hill Katherine , Stockfish Emily , Giantini-Larsen Alexandra , Alano Tina , Bale Tejus , Rosenblum Marc , Benhamida Jamal , Dunkel Ira , Berger Michael , Arcila Maria E , Ladanyi Marc , Miller Alexandra , Chakravarty Debyani , Solit David , Shukla Neerav , Karajannis Matthias
Published: June 2024

BACKGROUND

Genomic profiling and precision medicine have revolutionized cancer care but are not accessible to all due to high costs, insurance issues, limited access to testing facilities or qualified personnel. We established a program providing free clinical genomic testing worldwide (Make-An-IMPACT) and report findings from the pediatric CNS tumor cohort.

METHODS

Following a referral from: (1) a physician, (2) a disease-specific advocacy group, or (3) submission of contact information through program website, patients were enrolled on an IRB-approved protocol (NCT01775072). CSF cell free DNA (cfDNA) and matched normal samples were analyzed using MSK-IMPACTTM, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay. If a driver mutation wasn’t reported, raw genomic data was reviewed. OncoKBTM was used to determine the level of evidence supporting the clinical actionability of genomic aberrations.

RESULTS

24 patients (median age 7.5; range 0.1-20 years) were enrolled; 9 (38%) from 5 non-US countries and 6 (25%) from non-NYC US sites. African American and Hispanics constituted 8% and 13% of the cohort. Potentially actionable alterations were identified in 4/24 (17%) cases; 2/24 (8%) subsequently received matched therapy. In unbiopsied or non-diagnostic cases, a disease defining alteration was identified in 8/15 (53.3%). BRAF-KIAA1549 fusions were identified in 2/3 DLGNT patients and 1p loss in all 3. Both patients with BRAF fused DLGNT started targeted therapy with Trametinib, one of whom achieved a durable treatment response for 2.5 years. 3/8 patients with unbiopsied brainstem lesions had a H3.3K27M mutation, while 2 had non-H3.3K27M mutations detected (1 SMARCB1 deletion, 1 IDHR172G mutation) leading to treatment regimen changes.

CONCLUSIONS

This study captured a broad range of pediatric CNS malignancies with a diverse patient representation across geographic regions. CSF cfDNA profiling provided important diagnostic and therapeutic information reported in real time to patients and local physicians.
DEI-03. COMPASSIONATE USE OF NOVEL AND TARGETED THERAPIES IN RELAPSED AND PROGRESSIVE MALIGNAT PEDIATRIC BRAIN TUMORS: EXPERIENCE OF A SINGLE INSTITUTION
Authors: Solano-Páez Palma , Moreno-Madueño Gloria , Quiroga-Cantero Eduardo , Rivero -Garvia Mónica , Alvarez-Vayo Concepción
Published: June 2024

BACKGROUND

Off-label use of targeted therapy in pediatric Neuro Oncology is often offered to patients in the absence of available Clinical Trials specifically designed to this population. We present here six pediatric patients diagnosed with a malignant brain tumor who received compassionate treatment with targeted/novel therapy, alone or in combination, at disease progression or relapse, in a palliative setting.

METHODS

Retrospective chart review of patients diagnosed with a malignant brain tumor harboring a targeted molecular alteration, who received compassionate prescription of novel therapies not approved for the specific indication, and that were no eligible for a clinical trial. Patient demographics, dose of treatment delivered, tolerance, adverse effects, length of treatment, reason to discontinue the drug and survival rates were analyzed.

RESULTS

Four girls and two boys were identified; Median age at initiation of off-label drug: 4 years (3-17). Tumor type and targeted therapy delivered: DIPG H3 mutant (2), Diffuse Midline Glioma H3 and FGFR mutant (1), SHH-Medulloblastoma (1), ATRT (1), Diffusse Glioma EGFR and MET mutant (1). Off label drugs prescribed were ONC201, Erdafinitib, Sonidegib, Tazemetostat, and combination of crizotinib and erlotinib, respectively. Adverse events were mainly grade 1 and 2, however, 2/6 patients required hospital admission to manage adverse effects related to the experimental drug. One patient discontinued the drug due to side effects. All patients died of disease progression at a median of six months.

CONCLUSIONS

The anecdotical use of compassionate use of experimental drugs do not allow to gather clinical experience or to demonstrate a clinical benefit or impact in survival. Although the tolerance was generally good, the potential side effects caused by off-label drugs in a palliative population deserves a thorough individual assessment for its indication. Urgent need of targeted and novel therapies is warranted for pediatric children with malignant brain tumors.
DEI-06. IMPROVING ACCESS TO POST-MORTEM BRAIN TUMOR TISSUE DONATION BEYOND THE INPATIENT HOSPITAL SETTING
Authors: Lyons Nicole , Nazarian Javad , Eze Augustine , Nourmohammadi Niku , Koptyra Mateusz , Resnick Adam , Minturn Jane , Frenkel Beth , Reingruber Sonora , Wanders Angela , Bornhorst Miriam , Williams Melissa , Monje-Deisseroth Michelle , Hysinger Jared , Liljensten Ann-Helen , Souweidane Mark , Greenfield Jeffrey , Campbell Cindy , Padilla Christopher , Smith Amy , Peck Sydney , Vitanza Nick , Leary Sarah , Stevens Jeff
Published: June 2024

Between May 2021 and December 2023, approximately 33% of patients were being treated inpatient at the time of consent for post-mortem tissue donation through Gift From A Child. In the past, a major obstacle preventing families from donating post-mortem tissue was the inability to leave the hospital. Care teams and patient families are often concerned that in order to donate, the patient would have to pass away at the hospital. This creates a situation where the desire to donate comes at the cost of patient care and comfort. Through GFAC, children can pass at home, hospital, or hospice and still donate tissue successfully. The ability to donate post-mortem tissue is independent of patient location, ensuring that the focus of the family and care team remains on the child’s care rather than donation logistics. Additionally, patients can successfully donate tissue independent of status at the time of inquiry (declining, stable, urgent). The ability to quickly access a resource at a low burden to the family has been crucial in allowing tissue donation to happen. This also improves patient equity by eliminating access to hospital resources as a reason for a patient family to be required to live near a hospital. This is oftentimes a tremendous financial difficulty for patient families. Through establishing standard operating procedures and appointing tissue navigators, GFAC has streamlined what was previously an extremely complicated process mired in logistical obstacles. Patient families now have access to an efficient process for tissue donation. Previously, families would need to navigate complicated logistics unsupported, now they (or someone on their behalf) only need to contact GFAC or a Research Center of Excellence via phone or email and consent for donation. This ensures that post-mortem tissue can be donated easily, efficiently, and from wherever the patient family chooses.
TRLS-02. SAFETY AND EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394; PLX8394) IN CHILDREN AND ADULTS WITH RECURRENT, BRAF-ALTERED PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)
Authors: de la Fuente Macarena , Butowski Nicholas A , Taylor Jennie , Yaeger Rona , Tsai Frank Y-C , Janku Filip , Allen Carl E , Ammakkanavar Natraj , Michelson Glenn , Jiang Ping , Samara Emil , Paz Michael , Tussay-Lindenberg Alexia , Wang Kongming , Shepherd Stacie P , Kline Irina , Sherman Eric , Rodon Jordi
Published: June 2024

BACKGROUND

Plixorafenib is a selective, potent BRAFi that inhibits V600 and non-V600 alterations by disrupting BRAF monomers/dimers. Plixorafenib evades paradoxical MAPK pathway activation, eliminating the need for MEKi combination, and is potentially less prone to toxicities and resistance typical of approved BRAFis.

METHODS

Phase 1/2a study (NCT02428712) in children (n=5, aged 4-17 years) and adults (n=108) with BRAF-altered solid tumors assessing safety, PK, and efficacy of oral plixorafenib 900-3600mg/day ± cobicistat (PK enhancer).

RESULTS

Five children, 3 LGG (1 V600E, 1 fusion, 1 amplification), 1 neuroblastoma (G469A) and 1 ND-LCH (V600E), 4-8 prior therapies, received plixorafenib 300-1200 mg/day without cobicistat. Four received BSA-adjusted dosing, which delivered lower exposures than RP2D. All had SD, with duration 66.9+ months for ND-LCH. The fifth (neuroblastoma, 1200 mg/day) had PD. No DLTs, dose reductions, or LFT elevations. One had possibly related Grade 3 headache. Of 9 evaluable MAPKi-naïve adults with V600E PCNST, 4/5 with HGG and 2/4 with LGG/GNT responded; ORR 67% (95% CI: 29.9-92.5), mDOR 13.9 months. Responses in patients with only non-enhancing lesions and/or pilocytic astrocytoma indicate clinically relevant CNS penetration. Responses occurred across V600 solid tumors, ORR 42% (10/24); 1-year PFS 54.4%, 2-year PFS 48.4% in the MAPKi-naïve (non-CRC) subgroup. Of 14 evaluable adults with fusions, 2 responses (melanoma: CR, DOR 62.6+ months; PTC: PR, DOR 4.0+ months), 8 SD (5 with PCNST), 5 PD (3/5 with co-occurring driver mutations). Safety, efficacy, and PK in adults and children and insight into factors affecting plixorafenib exposure (not age or weight dependent) determined the optimal RP2D of plixorafenib as 900 mg QD with cobicistat for ages ≥10 years.

CONCLUSIONS

Plixorafenib had low rates of symptomatic TEAEs with a manageable safety profile, and high ORR in MAPKi-naïve BRAFV600 PCNST. A phase 2 study in children and adults is ongoing (NCT05503797).
TRLS-04. EARLY INSIGHTS FROM PNOC027: PERSONALIZED TREATMENT APPROACHES BASED ON REAL-TIME DRUG SCREENING AND GENOMIC TESTING IN PEDIATRIC AND ADOLESCENT PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Shatara Margaret , Paul Megan R , Long-Boyle Janel R , Meyer Ashley , Raber Shannon , Yeh-Nayre Lanipua , Jalkanen Aimee , Kilburn Lindsay B , Packer Roger J , Elster Jennifer D , Reddy Alyssa T , Koschmann Carl , Kraya Adam , Resnick Adam C , Prados Michael , Kline Cassie , Mueller Sabine , Wechsler-Reya Robert J , Rubin Joshua B
Published: June 2024

BACKGROUND

PNOC027, a clinical trial conducted by the Pediatric Neuro-Oncology Consortium (PNOC), explores a precision medicine strategy with up to four FDA-approved agents integrating real-time drug screening with whole exome DNA and RNA sequencing to guide personalized treatment approaches for children and young adults with relapsed medulloblastoma.

METHODS

Freshly isolated tumor cells from patients undergo high-throughput drug screening, evaluating responses to 232 clinically available compounds over 72 hours. In vitro drug responses are integrated with tumor genomic and transcriptomic data to predict drug combinations for each patient. Drugs are prioritized based on blood-brain barrier permeability, patient age, prior treatments, and other co-morbidities. Correlative studies include the collection of blood to assess circulating tumor DNA (ctDNA) before surgery and during treatment. Health-related quality of life (HRQOL) assessments will also be collected during therapy.

RESULTS

To date, nine patients have been enrolled. Eight of these have successfully completed real time drug screening with a median turnaround of 7 days from sample receipt. One patient was excluded due to ineligible (non-medulloblastoma) pathology after enrollment. Seven of these had whole exome sequencing, and six had RNA sequencing. Tumor board recommendations were rendered within 21 business days from the date of surgery. Among the diverse drug classes evaluated, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anthracyclines, DNA crosslinkers, and kinase inhibitors showed the most robust in vitro responses. Six patients received the recommended regimens, experiencing tolerable (grade 1/2) toxicities. Two patients succumbed to disease prior to therapy initiation, three exhibited disease progression while on therapy, and three remain on therapy.

CONCLUSION

PNOC027 demonstrates preliminary feasibility of real-time drug screening combined with DNA/RNA sequencing to inform targeted therapy selection in clinically relevant timeframes and with potential for disease response.
TRLS-05. A PILOT STUDY TO ASSESS THE SAFETY, FEASIBILITY, AND PRELIMINARY EFFICACY OF A NEOEPITOPE-BASED PERSONALIZED DNA VACCINE APPROACH IN PEDIATRIC PATIENTS WITH RECURRENT BRAIN TUMORS
Authors: Shatara Margaret , Rocco Abbey , Beck Mary , McHugh Michele , Lampe Ashley , Meyer Ashley , Ogle Andrea , Brossier Nicole M , Cluster Andrew , Rubin Joshua B , Abdelbaki Mohamed S
Published: June 2024

BACKGROUND

Pediatric brain tumors present a heterogeneous group of neoplasms with limited treatment options, especially at relapse. Hence, innovative therapeutic strategies are imperative. Immunotherapy, specifically immunogenomics, utilizing personalized vaccines based on tumor-specific neoantigens, has emerged as a promising option in other tumors. However, the feasibility of this approach in pediatric brain tumors remain largely unexplored.

METHODS

This single institution feasibility study focuses on sequencing analyses of pediatric brain tumors to identify mutant tumor-specific antigens. The study employs tumor/normal exome sequencing and cDNA-capture sequencing to identify and confirm mutant antigens, respectively. An epitope prediction algorithm prioritizes these antigens with subsequent confirmation of binding to HLA class I molecules. The neoantigen DNA vaccine strategy, utilizing a polyepitope DNA vaccine, is designed to target up to 20 prioritized antigens. The TDS-IM v2.0 device facilitates the administration of the vaccine. The primary objective of the study is to determine the feasibility of adjuvant personalized neoantigen DNA vaccine administration in patients with recurrent or refractory pediatric brain tumors.

RESULTS

We anticipate the identification of actionable neoantigens in pediatric brain tumors to support the potential efficacy of personalized DNA vaccines. The proposed sequencing strategies, epitope prediction algorithm, and in vitrobinding studies aim to establish a comprehensive methodology for neoantigen identification and prioritization. During the meeting, we will present the study background, rationale, detailed methodology, and design to inform the brain tumor community of this study.

CONCLUSION

This feasibility study is poised to provide essential insights into the development of personalized neoantigen DNA vaccines for recurrent or refractory pediatric brain tumors and aims to demonstrate safety, feasibility, and potential efficacy in targeting mutant tumor-specific antigens. The findings from this study will lay the groundwork for future clinical trials, evaluating the impact of personalized immunotherapy on progression-free and overall survival rates in this challenging patient population.
TRLS-06. PHASE 1 STUDY OF THE CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M (SOTIGALIMAB) IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE CNS TUMORS AND NEWLY DIAGNOSED BRAIN STEM GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-051; NCT03389802)
Authors: Lindsay Holly B , Billups Catherine , Baxter Patricia , Hwang Eugene , Lenzen Alicia , MacDonald Tobey , Pollack Ian F , Robison Nathan , Vinitsky Anna , Poussaint Tina Young , Onar-Thomas Arzu , Fangusaro Jason , Dunkel Ira J
Published: June 2024

BACKGROUND

CD40 is a co-stimulatory receptor present on antigen-presenting cells. CD40 agonists are hypothesized to reverse cancer-induced immune suppression and induce tumor cell killing. The PBTC completed a first-in-pediatrics phase 1 study (PBTC-051) of the CD40 agonistic monoclonal antibody APX005M (sotigalimab).

METHODS

Patients 1-21.99 years old with recurrent/progressive/refractory malignant non-brainstem central nervous system (CNS) tumors were eligible for stratum 1, and those with post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) for stratum 2. Patients received APX005M (sotigalimab) via IV on day 1 of each 21 day cycle. A 3 + 3 statistical design was used for dose escalation through 3 planned dose levels (DL). Patients could receive APX005M (sotigalimab) for 36 cycles or until disease progression, unacceptable toxicity, or death.

RESULTS

31 eligible patients enrolled (20 on stratum 1, 11 on stratum 2) between 2018-2023; 29 were evaluable for dose finding. The most common diagnosis in stratum 1 was ependymoma (35%). DL3 (0.6 mg/kg) was the recommended phase 2 dose (RP2D) for stratum 1 and DL2 (0.3 mg/kg) for stratum 2. Five patients had dose limiting toxicities—two stratum 1 patients at DL3 and three stratum 2 patients at DL3. The most common grade 3+ adverse events at least possibly attributable to APX005M (sotigalimab) were lymphopenia, neutropenia, leukopenia, and increased ALT. Median number of cycles was 2 (1-36) for stratum 1 and 3 (1-19) for stratum 2. No patients had an objective response to APX005M. 6 month progression-free survival (PFS) for stratum 2 patients (calculated from start of treatment) was 30.7±12.8%; median PFS was 3.7 months.

CONCLUSIONS

APX005M was well-tolerated in pediatric patients with both recurrent/refractory/progressive CNS tumors and post-radiation pre-progression DIPG. A RP2D was established for both populations. Future studies of this agent in pediatric neuro-oncology patients should prioritize combination therapy.
TRLS-08. ROVER: A PHASE 1/2 TRIAL IN PROGRESS OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Authors: Abbou Samuel , Koschmann Carl , Kramm Christof M , Hoffman Lindsey M , Plant-Fox Ashley S , Abdelbaki Mohamed S , Bui Ashley , Casanova Michela , van Tilburg Cornelis M , Khuong-Quang Dong-Anh , Chi Susan N , Shi Hongliang , Bidollari Ilda , Hong Janet , Swamy Preethi , Roche Maria , Morgenstern Daniel A
Published: June 2024

BACKGROUND

Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50<2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration [IC50]=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe.

METHODS

ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to <18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
ETMR-12. INFANTILE CENTRAL NERVOUS SYSTEM JUVENILE XANTHOGRANULOMA WITH SOMATICCSF1R MUTATION - RESPONSIVE TO IMATINIB MONOTHERAPY
Authors: Martinez-Torres Valerie , Etienne Kayla , Di Long , Rosenberg Andrew , Gultekin Sakir , Dhir Aditi , McCrea Heather J , Gampel Bradley
Published: June 2024

BACKGROUND

Juvenile xanthogranuloma (JXG) of the central nervous system(CNS) is a rare non-Langerhans cell histiocytosis typically affecting children and young adults. CSF1R mutations have been reported for peripheral JXG but have not previously been reported in CNS JXG. Treatment of CNS JXG relies on maximal safe surgical resection followed by cytotoxic chemotherapy, radiotherapy and/or molecular targeted therapy involving MAPK signaling pathway. Imatinib has been effective in treating tenosynovial giant cell tumor with CSF1R mutations.

METHODS

Case Report

RESULTS

A 3 month old male presented with fever, lymphadenopathy, and macrocephaly (45.5cm, 99.97%) with bulging fontanelles. Head ultrasound revealed dilated ventricles and brain MRI demonstrated multiple dural-based masses, the largest measuring 6.6 x 5.3 x 5.7 cm was located along the right tentorium and caused obstructive hydrocephalus. Patient underwent right frontal endoscopic third ventriculostomy and choroid plexus cauterization to treat hydrocephalus and right parietal craniotomy to resect the superficial dural-based mass for tissue diagnosis. Pathology was most consistent with a JXG that harbored a somatic CSF1R (NM_001288705.3) mutation. DNA Methylation profiling was unmatched. PET scan was negative for non-CNS lesions. Due to the multiple masses on presentation, the surgical risks of resection of the largest lesion, as well as having a targetable mutation, we opted for medical therapy. As Pexidartinib, a selective CSF1R inhibitor, was not available for infants, patient was started on liquid imatinib 340 mg/m2/day monotherapy. Three months after initiation of imatinib, the smaller parietal lesions resolved and after six months, the largest mass continued to shrink (6.3 x 2.9 x 2.9 cm). Treatment has been well tolerated without adverse events or drug interruptions.

CONCLUSION

This is the first report of CNS JXG with a CSF1R mutation. Importantly, it demonstrates that imatinib is a potentially safe and effective form of monotherapy for this rare disease.
ETMR-14. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES AN ONCOGENIC PHOTORECEPTOR PROGRAM AS A TUMORIGENIC VULNERABILITY UNIFYING DISTINCT EMBRYONAL CNS TUMOR ENTITIES
Authors: Gudenas Brian , Englinger Bernhard , Liu Anthony P Y , Ahmad Sheikh Tanveer , Zhao Miao , Meredith David , Pfaff Elke , Paul Leena , Hadley Jennifer , Batts Melissa , Klimo Jr. Paul , Boop Frederick A , Gajjar Amar , Robinson Giles W , Orr Brent A , Lin Hong , Alexandrescu Sanda , Jones David T W , Swartling Fredrik , Filbin Mariella G , Northcott Paul A
Published: June 2024

BACKGROUND

Pineoblastoma (PB) is a rare and aggressive childhood brain tumor with highly variable outcomes. PB is diagnostically characterized by expression of the photoreceptor identity transcription factor CRX, while tumors can be further classified into molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1), each marked by unique clinico-molecular features. However, developmental origins of PB subgroup heterogeneity and mechanisms governing malignancy remain unknown.

METHODS

We assembled a single-nucleus RNA-sequencing cohort (n=25) of primary PB tumors, including cases from all subgroups. A single-cell transcriptional atlas of the mouse pineal gland, covering 11 developmental stages (E11-P21), was created as a reference to map PB subgroup origins. Developmental trajectory analysis in the pineal gland showed a progression from pinealocyte progenitors to an early-, mid- and mature stage of pinealocyte differentiation.

RESULTS

Cross-species bioinformatics identified significant associations between PB subgroups and pinealocyte progenitors, mitotic cells expressing Crx, Otx2 and Neurod1. Single-nuclei gene regulatory networks in PB tumors identified CRX, OTX2, and NEUROD1 as master regulators of an oncogenic photoreceptor program conserved across PB subgroups. Surprisingly, this photoreceptor program was also highly expressed in retinoblastoma (RETB) and Group3 medulloblastoma (G3-MB). The molecular association between PB, RETB and G3-MB was further supported by DNA methylation and bulk RNA-seq, suggesting up-regulation of the oncogenic photoreceptor program is a unifying molecular connection of distinct CNS tumor entities. Querying this photoreceptor program across the developing pineal gland, retina, and cerebellum, identified conserved yet transient expression within each developmental lineage, suggesting the photoreceptor program may be a developmental vulnerability. In-vivo dependency assays for Otx2 and Neurod1 performed in a novel genetically engineered mouse model of the PB-RB subgroup confirmed their selective essentiality in photoreceptor-positive tumors.

CONCLUSIONS

Collectively, these findings uncover the photoreceptor program as a shared oncogenic dependency underlying anatomically distinct embryonal CNS tumors and provide a path towards rational clinical translation.
ETMR-15. RECLASSIFICATION OF CHILDHOOD CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR: CLINICAL FEATURES AND OUTCOME
Authors: Simbozel Marie , Tauziède-Espariat Arnault , Saffroy Raphaël , Guillemot Delphine , Pierron Gaëlle , Hasty Lauren , le Lechapt Emmanuè , Chrétien Fabrice , Grill Jacques , Guerrini-Rousseau Léa , Abbou Samuel , Bolle Stéphanie , Bourdeaut Franck , Raimbault Sandra , Gourmel Antoine , Réguerre Yves , Pluchart Claire , Serre Jill , Faure-Conter Cécile , Blauwblomme Thomas , Beccaria Kevin , Puget Stéphanie , Varlet Pascale , Dufour Christelle
Published: June 2024

BACKGROUND

The “central nervous system primitive neuroectodermal tumor” (CNS-PNET) nosology was removed from the World Health Organization (WHO) classification after DNA methylation profiling and new tumor entities characterized by specific recurrent genetic alterations were described. The aim of this study was to re-evaluate the diagnosis of CNS-PNET and to describe their clinical characteristics.

METHODS

Patients aged < 18 years with CNS-PNET or unclassified tumor, who were treated at Gustave Roussy between 1999 and 2019 or enrolled in the PNET HR trial were retrospectively identified. The study included all patients with sufficient archival material for diagnosis re-evaluation.

RESULTS

Sixty-two patients were eligible for the current analysis. The central histopathological review proposed a diagnosis according to the WHO classification in 58 cases. Out of these cases, 34 embryonal tumors were identified: 22 Embryonal Tumors with Multilayered Rosettes (ETMR), 4 CNS neuroblastomas with FOXR2 activation (CNS NB-FOXR2), 4 CNS high-grade neuroepithelial tumors with BCOR alteration (CNS HGNET-BCOR), 4 medulloblastomas. Another 24 tumors were classified as non embryonal tumors: 11 high-grade gliomas, 5 ependymomas, 4 pineoblastomas, 2 teratomas, one desmoplastic small round cell tumor, and one pilocytic astrocytoma. Four tumors without suspected diagnosis after first analysis remain unclassified after DNA methylation profiling. The 5-year event-free survival and overall survival for patients with ETMR were 14% (95% CI, 4.7-39%) and 27% (95% CI, 14-54%) respectively. For patients with CNS HGNET-BCOR and CNS NB-FOXR2 the median time to relapse was respectively 11 months (range, 0.5 to 1.3 year) and 3.1 years (range 1.7 to 4.4 years).

CONCLUSIONS

This study confirmed that the former nosology of CNS PNET does not correspond to a homogenous class but encompasses a diversity of rare histomolecular entities with specific clinical characteristics and outcomes.
ETMR-16. PEDIATRIC SPINAL EMBRYONAL TUMORS; PATHOLOGICAL INSIGHTS INTO THIS RARE ENTITY
Authors: Juneja Archita , Ranade Manali , Shetty Omshree , Sahay Ayushi , Shah Aekta , Prasad Maya , Chinnaswamy Girish , Sahu Arpita , Singh Vikas , Shetty Prakash , Moiyadi Aliasgar , Dasgupta Arychya , Chatterjee Abhishek , Gupta Tejpal , Epari Sridhar
Published: June 2024

BACKGROUND

Spinal cord is an extremely uncommon primary location for the CNS embryonal group of tumours. This study aims to collate the immunohistological spectrum of these rare spinal CNS embryonal tumours, diagnosed in the institute during the last 20 years.

METHODS

Of the total 446 spinal tumours, 15 were embryonal tumours. Of these, 5 were metastases, four from medulloblastoma and one from AT/RT (diagnosed subsequently) which were excluded and thus the study cohort comprised 10 cases. Eight were atypical teratoid/rhabdoid tumour (AT/RT; 80%), and 2 were embryonal tumour with multilayered rosettes (ETMR; 20%).

RESULTS

Six AT/RT cases were of ≤2 years age; while other two were 6 and 11 years of age with a M:F ratio of 1.3:1 (thoracic: 4; cervical: 2; lumbar: 2). Histologically, rhabdoid-like morphology (87.5%), necrosis (100%), and calcification (25%) were noted. All of them were of INI1 protein (SMARCB1)-deficient., all of them were negative for brachyury and all were variably positive for AE1/AE3. Two ETMR cases were of <2 years of age, females and at lumbar and cervical levels respectively. C19MC amplification by FISH was done for one case which was not amplified. Histologically, one of them showed a medulloepithelioma-like pattern; while the other showed multilayered rosettes and neuropil-like matrix. LIN28A strong positivity, retained nuclear staining for INI1 protein and negativity for AE1/AE3 was noted in both. Significant BCOR positivity was seen in one but was negative for SATB2.

CONCLUSIONS

Spinal embryonal tumours are extremely rare and metastases needs to be ruled out before considering as primary. AT/RT is the most common embryonal tumour in the spine, commonly SMARCB1(INI1)-deficient. ETMR can also encountered in the spinal location.
ETMR-20. CARDIOLIPIN ACYL CHAIN MODULATION AS A NOVEL MITOCHONDRIAL-FOCUSED THERAPEUTIC TARGET IN ETMR
Authors: Liapis Evangelos , O’Neill Kelly C , Pamreddy Annapurna , Maas Allison , Hanson Derek R , Carter Claire L
Published: June 2024

Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm that occurs almost exclusively in infants and is associated with an extremely poor prognosis. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the initiation and progression of diverse cancers and studies have linked metabolic rewiring to chemotherapy resistance. Cardiolipins are mitochondrial-specific lipids that reside in the mitochondrial membrane and their fatty acid composition has been extensively shown to regulate mitochondrial function and dynamics. Despite the known functional significance of cardiolipin structure, their role in mitochondrial regulation of brain tumors remains ill-defined. Using mass spectrometry imaging, we identified a shift to shorter acyl chain cardiolipins within the rapidly proliferating embryonal tumor cells in patient samples and patient-derived cell lines grown as 3D tumorspheres. Western blot analysis of the enzymes involved in cardiolipin synthesis and remodeling identified a significant increase in the expression of the cardiolipin remodeling enzyme, LCLAT1/ALCAT1. Orthogonal imaging techniques including immunohistochemistry, transmission electron microscopy and super-resolution microscopy correlated shorter acyl chain remodeling of cardiolipin with fragmented mitochondria (increased fission) and aberrant cristae structure. Further studies identified increased expression of the fission protein Drp1, decreased expression of respiratory chain enzymes and altered respiration in the embryonal tumor cells. Ongoing studies will utilize multiple methods to modulate cardiolipin acyl chain structure and use MS and MSI to correlate cardiolipin fatty acid structure to mitochondrial function and growth inhibition in the embryonal tumor cells.
ETMR-24. SOX2 INFLUENCES IDENTITY OF GLIA-LIKE PROGENITORS AND TUMORIGENESIS IN CHOROID PLEXUS THROUGH LIM HOMEODOMAIN TRANSCRIPTION FACTORS
Authors: Faltings Lukas , Zahran Mariam , Jalili Heena , Green Kristen , Virga James , Modi Siddhi , Guru Navjot , Cao Ping , Zhao Haotian
Published: June 2024

Choroid plexus (CP) tumors encompass a spectrum of rare brain neoplasms ranging from benign papilloma (CPP) to aggressive carcinoma (CPC) that collectively affect the pediatric population. Poor outcomes for high-grade lesions and side effects of current treatment paradigms underscore a critical need to develop safer and more efficacious therapies guided by biological understanding of these tumors. We developed mouse models from common molecular defects found in human disease. These models exploit sustained NOTCH signaling activation in the hindbrain upper rhombic lip to generate CPP and CPC. To delineate cellular composition of CP tumors, we conducted snRNA-seq in murine CP tumors. Similar to adult CP, cells in NOTCH-driven CPP partitioned into clusters identified as epithelial, mesenchymal, endothelial, immune, neuronal, and glial cells. Though tumor cells are confined to epithelial compartment based on inferCNV analysis of snRNA-seq data, they are derived from glia-like progenitors. Tumor cells are in a distinct differentiation state characterized by a lack of epithelial maturation, and aberrant expression of markers of neural progenitor/stem-like cells including SRY-Box Transcription Factor 2 (SOX2). Consistently, SOX2 inactivation decreased tumor cell proliferation and blocked NOTCH-driven CP tumor formation. ChIP-seq studies revealed SOX2 binding to promoters of LIM homeodomain transcription factors Lmx1a and Lmx1b. Enforced SOX2 expression activated the expression Lmx1a and Lmx1b, whereas Sox2 loss reduced their expressions in tumor cells. Importantly, knockdown of Lmx1a or Lmx1b decreased tumor cell proliferation, whereas overexpression of Lmx1a/b rescued proliferation of tumor cells subjected to SOX2 suppression. Contextualizing these results in CP development, SOX2 critically maintains progenitor cell identity through regulating Lmx1a/b expression in the rhombic lip. Finally, analysis of human CP tumor samples revealed abnormal expressions of SOX2 and LMX1A. Together, these results indicate that oncogenic signaling subverts SOX2 transcriptional programs that specify normal progenitor identity and lock tumor cells in unique differentiation state to facilitate CP tumor growth.
EPEN-05. SURGERY FOR CHILDHOOD EPENDYMOMA: THE EPENDYMOMA MULTIDISCIPLINARY ADVISORY GROUP (EMAG) CLINICAL TRIAL EXPERIENCE
Authors: Ritzmann Timothy A , Chapman Rebecca J , Leatherland Rheanne , Goodden John , Macarthur Donald , Mallucci Conor , Kamaly Ian , Pizer Barry , Grundy Richard G
Published: June 2024

INTRODUCTION

The National Ependymoma Multidisciplinary Advisory Group (EMAG) is the central review mechanism for the SIOP Ependymoma II clinical trial in the UK. EMAG is a multiprofessional group which meets weekly to support decision making. We report detailed surgical outcomes for children with confirmed intracranial ependymoma, discussed through EMAG between January 2020 and November 2022.

METHODS

Data was collected on resection status, surgical outcomes, reasons for not achieving Gross Total Resection (GTR), number of surgeries and adjuvant therapies. Data was analysed descriptively.

RESULTS

After first surgery, GTR or near total resection (NTR) rate was 69/105 (66%) rising to 83/105 (79%) following repeated surgeries. 17 patients underwent second-look surgery prior to further therapy, whilst 9 underwent second-look surgery after chemotherapy but before radiotherapy. Eight (17%) posterior fossa (PF) surgeries were not completed due to factors including patient instability and tumour attachments. Most post-operative problems were seen in PF tumours with 26/60 (43%) bulbar palsy, 13/60 (22%) focal weakness and 12/60 (20%) cerebellar mutism. Incomplete PF resections were associated with increased bulbar palsy risk (p=0.02, Chi-Square test). 73% of PF patients required hydrocephalus management with external ventricular drainage, endoscopic third ventriculostomy (ETV) or shunt. Longer term hydrocephalus management with ETV or shunt was required in 29% and was more common in those with subtotal resection (R3-RX, 8/16, 50%) compared to GTR or NTR (R0-R2, 9/43, 21%, p=0.03). 27/60 (45%) received post-op NG feeding and 2/60 (3%) needed tracheostomies. Second surgery was associated with lower complication rates.

DISCUSSION

Our National MDT approach supports collaborative surgical decision making without a need for centralisation of the surgery itself. There was no evidence of increased complication rates compared to historical trials despite a more aggressive surgical approach. We argue for continued centralisation of EPN evaluation to support optimal care for children with this devastating disease.
EPEN-08. MULTI-OMICS PROFILES REVEAL UNIQUE DEFINING MOLECULAR FEATURES OF POSTERIOR FOSSA EPENDYMOMA SUBTYPE A FROM INFANTS
Authors: Lourdusamy Anbarasu , Chapman Rebecca J , Ritzmann Timothy A , Grundy Richard G , Dineen Robert A
Published: June 2024

BACKGROUND

Ependymoma is a heterogeneous brain cancer with multiple subgroups based on locations and molecular profiles. Tumours of the methylation class, posterior fossa group A (PF-EPN-A) represent the most common and aggressive neoplasms and have a poor outcome. PF-EPN-A tumours in infants (under three years of age) are understudied; this project aimed to characterise these infant tumours.

METHODS

We collected DNA methylation (n=570) and gene expression (n=56) profiles of PF-EPN-A tumours, and single-cell RNA sequencing data of human fetal cerebellum from published studies.

RESULTS

Analysis of copy number profiles derived from DNA methylation arrays showed that infants with PF-EPN-A have relatively quiescent genomes when compared to children aged four to eighteen years (mean fraction of changes in infants (n=300) = 0.018 and children (n=270) = 0.055; p-value < 2.2 × 10-16). No recurrent focal amplifications or losses were detected, however, copy number loss involving chromosome arms, 12q (12%), 7q (9.7%), 5p (8.3%), and 16p (6%) were relatively common in infants, while 1q gain, 6q loss, and 22q loss were more frequent in children. When we stratified PF-EPN-A based on copy number alterations, infants with altered genomes were associated with poor outcomes compared to infants with stable genomes (fraction of changes = 0), which in turn showed poor overall survival compared to children with stable genomes. Gene set enrichment analysis using data from microarrays showed that infant tumours were specifically enriched with genes involved in the extracellular matrix organization, interferon gamma signaling, neuronal system, autophagy, and signaling by Interleukins, VEGF and PDGF. Integration with single-cell data from the human fetal cerebellum revealed that infants in PF-EPN-A had significantly higher proportions of glial progenitor cells and decreased granule cell progenitor subpopulations.

CONCLUSIONS

Together, our study identifies distinct genetic and transcriptional programs among infants in PF-EPN-A tumours, representing opportunities to refine future treatment.
EPEN-13. PRE-IRRADIATION CHEMOTHERAPY EXPERIENCE FOR PEDIATRIC EPENDYMOMA POLISH PROTOCOL
Authors: Filipek Iwona , McGlynn Mary Claire , Drogosiewicz Monika , Tarasińska Magdalena , Perek-Polnik Marta , Kowalczyk Paweł , Święszkowska Ewa , Grajkowska Wiesława , Abdelbaki Mohamed S , Dembowska-Bagińska Bożenna , Trubicka Joanna
Published: June 2024

BACKGROUND

Pediatric ependymomas are aggressive central nervous system malignancies arising from the ependymal linings of ventricles and spinal canal. Despite better understanding of tumor biology ependymomas remain therapeutic challenge in pediatric neurooncology. The role of chemotherapy remains controversial. Herein, we describe the outcomes of patients treated at the largest center in Poland who underwent surgery, pre-irradiation chemotherapy and irradiation regardless of extent of surgical resection.

METHODS

This retrospective review includes pediatric patients with ependymoma treated according to national protocol at the Children’s Memorial Health Institute. We reviewed histology, disease extent, treatment, and report on overall survival (OS) and progression free survival rates (PFS). Descriptive statistics were analyzed using SPSS software.

RESULTS

Forty-nine patients were included (median age: 84 months). Most patients (96%) had cranial ependymomas (43% supratentorial and 57% posterior fossa lesions). Disseminated disease was found in 16% of cases. Complete resection was achieved in 43%. All patients received pre-irradiation chemotherapy; 6.1% had progressive disease and 41% achieved complete response (CR). All patients, except one, underwent irradiation (67% focal, 2% focal/ventricular, 29% craniospinal, and 2% whole brain). Thirty-five percent of patients relapsed. Five-year PFS and OS were 69% and 80% respectively. Comparing posterior fossa to supratentorial lesions, there was no difference in response after surgery and pre-irradiation chemotherapy (CR 37% versus 50% (p=0.51)) or irradiation (CR 42% versus 55% (p=0.37)). However, relapse was more likely in posterior fossa ependymomas (OR 0.30 IQR (0.70, 1.29), p=0.03) with lower 5-year PFS (56% versus 85%, p=0.03) and 10-year PFS (52% versus 85%, p=0.02). The benefit of chemotherapy was marked in patients with Grade 3 (5-year OS 82% versus 69%)

CONCLUSIONS

We describe a large cohort of pediatric ependymoma patients who received pre-irradiation chemotherapy. This strategy did not negatively impact the incidence of progression before irradiation.