antibodies

2026-07-29 | Primary Intraspinal Extradural Tumor Previously Classified as Primitive Neuroectodermal Tumor: Clinical and Imaging Findings: A Case Report

Primitive neuroectodermal tumors are aggressive childhood neoplasms that primarily arise in the Central Nervous System and rarely occur in the spine, and are currently reclassified within embryonal tumor groups. We present a case of a 15-year-old male with lower extremity weakness and sphincter dysfunction. Spinal magnetic resonance imaging revealed a well-defined extradural mass at thoracic (Th) 11–L1 with extraspinal extension and spinal cord compression. The tumor was completely resected, and histopathology was consistent with Primitive Neuroectodermal Tumor (former classification) although additional markers were inconclusive due to technical limitations. Neurological recovery was favorable. Sphincter dysfunction resolved by the time of hospital discharge, and lower extremity weaknes progressively improved, with near complete recovery at 3-month follow-up. However, seven years later, the tumor recurred and required repeat surgical treatment. This case highlights the importance of magnetic resonance imaging in the diagnosis, assessment of disease extent, and long-term follow-up of rare spinal embryonal tumors.

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2026-06-23 | ID #744 Epidemiological profile of central nervous system tumors in patients followed at the neuro-oncology outpatient clinic of ITACI (1994-2025)

Abstract Introduction Central nervous system (CNS) tumors are a major cause of morbidity and mortality in children and adolescents, often leading to neurological sequelae and reduced quality of life. In Brazil, epidemiological data from specialized centers remain scarce, limiting public health planning. The Instituto de Tratamento do Câncer Infantil (ITACI) is a national reference center in pediatric oncology. This study aimed to describe the epidemiological profile of CNS tumors treated at ITACI. Methods This retrospective, descriptive study analyzed the institutional database of the ITACI neuro-oncology outpatient clinic. All patients with confirmed CNS tumors followed between 1994 and 2025 were included. Variables analyzed were histological diagnosis and diagnostic frequency. Data were evaluated using descriptive statistics and expressed as absolute and relative frequencies. Results A total of 468 patients were analyzed, with slight male predominance (52.78%; n = 247). There was a progressive increase in diagnoses over time, with higher frequencies in recent years, especially 2025 (13.68%) and 2023 (12.61%). The category “Others”, grouping rare tumors, represented the most frequent diagnosis (18.80%; n = 88), reflecting the heterogeneity of CNS neoplasms. Among specific tumors, medulloblastoma was most prevalent (17.52%; n = 82), followed by pilocytic astrocytoma (11.54%; n = 54), low-grade gliomas (7.69%; n = 36), ependymomas (6.62%; n = 31), and germ cell tumors (5.77%; n = 27). Other relevant diagnoses included optic pathway gliomas, craniopharyngiomas, diffuse brainstem gliomas, and high-grade gliomas. Conclusion The study demonstrated an epidemiological pattern consistent with the literature, with predominance of embryonal and glial tumors and slight male predominance. The high frequency of rare tumors highlights the importance of specialized centers for accurate diagnosis and management. These findings reinforce ITACI’s role as a national reference center and contribute to Brazilian epidemiological data, supporting healthcare planning and public policy development in pediatric neuro-oncology.

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2026-05-08 | Immune checkpoint inhibitors in medulloblastoma: current updates in preclinical and clinical developments

Medulloblastoma (MB) is the most common pediatric embryonal tumor of the central nervous system. MB grows rapidly in the cerebellum and causes devastating disease in young children. The presence of high-risk molecular or histopathological features is associated with frequent recurrence, resistance to therapy, and poor prognosis, with few experiencing long-term survival. The current standard of care for MB includes surgical resection, radiation, and chemotherapy; however, there remains a need for more specific and effective treatment strategies, especially in recurrent disease. Promising developments in immune checkpoint inhibition have recently entered clinical trials, yet few address MB. Classic immune checkpoints such as Programmed Cell Death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) have recently been identified as potential therapeutic targets for slowing MB progression in the recurrent setting. Preclinical and clinical studies have identified additional targets such as B7-H3, V-domain Ig Suppressor of T-cell Activation (VISTA), lymphocyte-activated gene 3 (LAG-3), P-selectin glycoprotein 1 (PSGL-1), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) expression in the MB TME. This review summarizes current preclinical and clinical prospects for immune checkpoint inhibition via direct antibody targeting for the treatment of MB and describes the proposed next generation of immune checkpoint inhibitors.

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2026-03-23 | A Rare Thoracolumbar Spinal Atypical Teratoid/Rhabdoid Tumor in a 7-Year-Old Child: Diagnostic Challenges and Therapeutic Considerations

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal neoplasm of the central nervous system, primarily diagnosed in children under three years of age, with spinal presentations accounting for fewer than 2% of patients. This report describes an unusual primary thoracolumbar spinal AT/RT in a 7-year-old girl who presented with severe, rapidly progressive pain impairing mobility. Magnetic resonance imaging revealed a large intradural extramedullary mass extending from T11 to L3 with marked compression of the conus medullaris and cauda equina. Surgical resection was performed, and histopathological evaluation confirmed rhabdoid morphology with characteristic immunophenotypic features, including loss of nuclear SMARCB1 (INI1) expression and elevated proliferative index, consistent with AT/RT. This case report highlights the diagnostic complexity due to overlapping features with other pediatric spinal tumors, necessitating comprehensive histological, immunohistochemical, and molecular analyses for accurate classification. Discussion integrates the patient tumor profile within the framework of WHO 2021 molecular subgroups, underscoring the clinical heterogeneity and poor prognosis associated with spinal AT/RT, particularly the aggressive AT/RT-MYC subtype. Despite maximal surgical and multimodal therapy, outcomes remain dismal, emphasizing the urgent need for collaborative research exploring targeted molecular and immunotherapeutic strategies. This case report expands limited literature, offering valuable insights for early recognition and management of spinal AT/RT in older pediatric patients.

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2025-10-01 | Forty years of follow-up: Incidence, diagnoses and long-term survival in children diagnosed with central nervous system tumors in Sweden 1984-2021

Abstract Background Central nervous system (CNS) tumors are the second most common childhood malignancy and a leading cause of cancer-related mortality. This national population-based study describes childhood primary CNS tumors diagnosed in Sweden over 40 years, incorporating the latest WHO classification and long-term survival data. Methods All primary CNS tumors in children (0-14 years), diagnosed between 1984 and 2021 and registered in Swedish Cancer Registries, were reviewed. Data on tumor location, histology, and the reclassified supratentorial CNS-PNETs were incorporated. Tumors were categorized according to the International Classification of Childhood Cancer, third edition. Incidence and survival rates were analyzed. Results Overall, 2954 children (<15 years) were diagnosed with a CNS tumor in Sweden 1984-2021. The average incidence rate was 4.6/100 000 children per year, and it remained stable during the study period. Astrocytomas constituted 49%, embryonal tumors 17%, and ependymomas 7% of cases. Five-year overall survival improved from 75% to 82% over the study period. However, several tumor types showed a continued decline in survival at 30 years of follow-up. Conclusions This 40-year population-based study provides comprehensive data on childhood CNS tumors in Sweden. The incidence remained stable during the 4 decades. The distribution of tumor diagnoses is in line with other countries. Survival has improved over time, but for some diagnoses, late mortality is seen many years after primary diagnosis, highlighting the importance of long-term follow-up.

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small molecules

2026-06-30 | High-dose chemotherapy with autologous stem cell rescue in children under 5 years of age with central nervous system embryonal tumors: results from a prospective cohort in an upper-middle-income country

PURPOSE: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been employed to mitigate the long-term side effects of radiotherapy and improve survival outcomes in infants with embryonal central nervous system (CNS) tumors. METHODS: This prospective study, supported by federal funding from the National Oncological Care Support Program, included children younger than 5 years of age with newly diagnosed CNS embryonal tumors treated with surgery and HDCT/ASCR. RESULTS: Between 2016 and 2019, 36 patients were included: 22 with medulloblastoma (MB) and 14 with other CNS embryonal tumors. In the MB cohort, the mean age was 2.5 years, 13 were male. Gross total resection (GTR) was achieved in 18 patients; 15 had non-metastatic disease (M0). Among non-MB patients, the mean age was 2.7 years, 11 were female. Nine patients had GTR; 12 had M0. According to the MB molecular subgroup, the 2- and 5-year event-free survival (EFS) rates for the SHH subgroup were 76.9%, and overall survival (OS) was 92.3%. For the non-WNT/non-SHH subgroup, the 2- and 5-year EFS rates were 33.3% and 22.2%, and OS, 66.7% and 55.6%, respectively. Two SHH and five non-WNT/non-SHH patients were successfully salvaged with craniospinal irradiation after a mean of 12 months (range, 7-36 months). Among non-MB patients, the 2- and 5-year EFS and OS were 28.6/19.0% and 42.9/32.1%, respectively. All patients developed grade 3-4 mucositis/typhlitis and febrile neutropenia and 13.9% invasive fungal infections during HDCT. CONCLUSION: HDCT/ASCR is feasible in a middle-income country setting and provides favorable outcomes in SHH medulloblastoma. However, prognosis remains poor for non-SHH MB and other embryonal tumors, highlighting the need for novel molecularly guided therapies.

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2026-06-23 | ID #662 Treatment approaches for CNS tumors with BCOR ITD

Abstract High grade neuroepithelial tumors of the central nervous system (CNS) with BCL-6 corepressor (BCOR) with internal tandem duplication (ITD) are rare and aggressive pediatric tumors without standardized treatment options. These tumors are histologically embryonal tumors and molecular profiling is necessary to establish the diagnosis. These patients are treated per available case reports and case series. We are presenting our institutional experience with two cases. Case1 2-year-old presented with right hand weakness. Imaging showed mass measuring 10.6cm arising from left cerebral hemisphere, negative spine imaging. She underwent gross total resection (GTR). Pathology showed high-grade neuroepithelial tumor with BCOR ITD. Treated per Children’s Oncology Group protocol ACNS0334 with three intensive induction cycles and three autologous transplants. Two years later she presented with right-sided hemiplegia and partial seizure. Imaging showed a 2.1cm nodule in the surgical bed with hemorrhage. Underwent GTR, craniospinal irradiation to 26.3Gy, tumor boost to 56.5Gy and chemotherapy with bevacizumab, irinotecan and temozolomide, and now in remission over 6 years from recurrence. Case 2 2-year-old presented with headache and abnormal gait and found to have a right frontal lobe mixed solid and cystic mass, negative spine imaging. Bifrontal craniotomy was performed to achieve GTR. The pathology showed malignant CNS tumor with BCOR ITD. The patient was treated similarly to case 1 with three intensive induction chemotherapy cycles followed by high-dose chemotherapy with autologous transplant, and then focal radiation to the primary tumor site to 51Gy. The patient is in remission for the past 6 months. Conclusion Even though diagnostic challenges are being met through molecular profiling, the treatment options remain unstandardized. Both patients did well with a combination of intensive chemotherapy, autologous stem cell transplant and irradiation and remain disease-free. This case series emphasizes the need to standardize treatment approaches for CNS tumors with BCOR ITD.

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2026-06-23 | ID #396 High-Dose Chemotherapy with Autologous Stem Cell Rescue in Children under 5 Years of Age with Central Nervous System Embryonal Tumors: Results from a Prospective Middle-Income Country Cohort

Abstract High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been employed to mitigate long-term side effects of radiotherapy (RT) and improve survival of central nervous system (CNS) embryonal tumors in infants. Objective Characterize a cohort of patients treated with a transplant-based strategy in a middle-income country. Methods Prospective study supported by Federal funding from National Oncological Care Support Program for children under five years-old with CNS embryonal tumors. Results From 2016-2019, thirty-six patients were included: Twenty-two medulloblastomas (MB), six atypical teratoid/rhabdoid tumors, one pinealoblastoma, and seven other CNS embryonal tumors. Among the MB group, mean age was 2.5 years (1.5-4.8y), 13 were male. Eighteen had complete resection, fifteen had no metastasis (M0). Among non-MB patients, mean age was 2.7 years (0.7-2.9y), 11 were female. Nine had complete resection, 12 were M0. According to molecular subgroups, event-free-survival (EFS) rates at 2 and 5 years for SHH were 76.9% and overall (OS) 92.3%. For the non-WNT/non-SHH subgroup, EFS at 2 and 5 years were 33.3% and 22.2%, while OS were 66.7% and 55.6%, respectively. Both relapsed SHH patients had p53>50% on immunohistochemistry. Two SHH and five non-WNT/non-SHH patients were rescued with craniospinal RT and except for two non-SHH patients with metastatic relapses, the others are still alive without disease. Death occurred in one SHH patient due to meningitis, and two non-WNT/non-SHH during induction due to sepsis and disease progression. For all non-MB cases, EFS and OS at 2 and 5 years were 28.6%/19.0% and 42.9%/32.1%. All patients presented with mucositis/typhlitis and febrile neutropenia grade 3-4 during HDCT/ASCR. Conclusion HDCT/ASCR can be conducted in well-structured centers, even in countries with less resources as Brazil. Except for those with SHH-MB, the prognosis for infants with non-SHH MB and other CNS-embryonal tumors remains poor, highlighting the need for new treatment approaches.

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2026-06-23 | ID #933 OUTCOMES OF INFANTS AND YOUNG CHILDREN WITH NEWLY DIAGNOSED CENTRAL NERVOUS SYSTEM (CNS) EMBRYONAL TUMORS OTHER THAN MEDULLOBLASTOMA AND ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT), INCLUDING EMBRYONAL TUMOR WITH MULTI-LAYERED ROSETTES (ETMR), PINEOBLASTOMA (PB) AND CNS EMBRYONAL TUMORS NOS, TREATED ON THE “HEAD START” 4 PROTOCOL

Abstract Background “Head Start” 4 (HS-4) is a prospective clinical trial with a primary objective to determine whether tandem marrow-ablative Consolidation chemotherapy (HDCT), in a randomized comparison with single-cycle Consolidation, provides event-free and overall survival (EFS and OS) benefit for patients with non-Wnt/non-Shh medulloblastoma and Other central nervous system embryonal tumors (CNS-ETs) completing HS-4 Induction. We present the outcome of Other CNS-ETs enrolled on HS-4. Methods Fifty-one eligible patients with Other CNS-ETs, median age 2.61 years (range: 1.36-3.54), were enrolled on HS-4 (ETMR=21, PB = 13, Other CNS-ET NOS=17), and received three cycles (five cycles if < complete response) of Induction (vincristine/cisplatin/cyclophosphamide/etoposide/high-dose methotrexate) followed by randomization to either Consolidation with three tandem HDCT cycles (thiotepa/carboplatin) or single HDCT cycle (thiotepa/carboplatin/etoposide). Diagnosis was confirmed by central pathology review and DNA methylation. Twenty patients were deemed non-evaluable: progression=9, family/physician preference=8 and toxicity=3; all during induction. Results For Intent-to-Treat analysis of all 51 patients, the 2-year EFS and OS was 43.9% (95%CI: 31.6-61) and 53.6% (95%CI=41.3-69.5) overall, 39.7% (95%CI=22.4-70.3) and 38.1% (95%CI=22.1-65.7) for ETMR, 46.2% (95%CI=25.7-83.0) and 53.8% (95%CI=32.6-89.1) for PB, and 47.5% (95%CI=27.9-80.9) and 73.9% (95%CI=54.9-99.6) for Other CNS-ET NOS patients. For 31 evaluable patients completing Induction (ETMR=13, PB = 5, Other CNS ET, NOS=13), the 2-year EFS and OS were 60.1% (95%CI: 44.2-81.6) and 76.2% (95%CI=62.2-93.3) overall , 59.2% (95%CI=37.1-94.5) and 61.5% (95%CI=40.0-94.6) for ETMR, 80% (95%CI=51.6-100) and 100% for PB, and 51.9% (95%CI=28.7-93.9) and 82.1% (95%CI=62.1-100) for Other CNS-ET NOS patients. For 17 evaluable patients receiving three tandem HDCT cycles, 2-year EFS was 81.6% (95%CI=64.7-100), compared to 30% (95%CI=12-74.7) for 14 patients receiving single HDCT cycle (p = 0.0099). Conclusion We report excellent results for young children with Other CNS-ETs when treated with intensive Induction and HDCT Consolidation on HS-4 trial without irradiation, with improved EFS for patients receiving three tandem HDCT cycles.

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2026-04-24 | A modified multi-drug metronomic antiangiogenic approach in recurrent pediatric embryonal central nervous system tumors: an institutional experience

Abstract Background Approximately one third of pediatric patients with embryonal tumors of the central nervous system will experience a recurrence, with poor prognosis. Patients with recurrent or progressive disease may be treated with multi-drug metronomic antiangiogenic approaches. Methods We performed a retrospective review of 13 patients treated at a single institution from 2010-2023 using a multimodal metronomic antiangiogenic regimen which includes oral thalidomide, celecoxib and fenofibrate, and alternating etoposide/cyclophosphamide, intravenous bevacizumab, and alternating intraventricular etoposide, cytarabine, and topotecan. Results Toxicities included myelosuppression with at least one grade 3 hematologic toxicity in 11/12 (92%) patients. Other toxicities included infection, neurologic (cerebritis, irritability), hepatic (transaminitis), and a secondary leukemia. Seven patients required one or more drugs to be held or modified due to toxicity. The overall response rate was 69.2% (95% confidence interval (CI): 38.6%-90.9%) with median time to best response for patients who achieved CR or PR of 5 months. The median event-free survival (EFS) and overall survival (OS) time was 6 months (range: 1-21 months) and 15 months (range: 1.1-42.6 months), respectively. The 12-months EFS was 46.1% (95% CI: 19.2%-69.6%) with 12-months OS 83.9% (95% CI: 49.4%-95.7%). Conclusion Metronomic multi-drug approaches combining oral, intravenous and intraventricular/intrathecal therapy were generally well tolerated and provided a survival benefit.

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gene therapies

2026-06-24 | Guidance for the Diagnosis and Treatment of Rare Embryonal and Sarcomatous Brain Tumors—a Report from the Central Nervous System-International Registry for Rare Embryonal and Sarcomatous Tumors German Society of Pediatric Oncology and Hematology Study Group

Abstract: With the advent of multi-omic molecular profiling techniques, central nervous system tumor types previously not recognized by conventional neuropathological assessment have emerged, particularly among tumors formerly termed as "CNS- primitive neuroectodermal tumors." Given the diverse histopathological, molecular, radiological, and clinical characteristics of these tumors, diagnostic approaches and treatment strategies need to be adapted to our increasing knowledge. The small number of patients per year for individual tumor types precludes large cohort studies and mandates international cooperation and harmonization. To this end, the SIOPE Brain Tumor Group together with the European Reference Network for Pediatric Cancers has published the European Standards of Clinical Practice guidelines for rare embryonal and sarcomatous tumors.

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2026-03-28 | Early Recurrence of an Adult Desmoplastic Medulloblastoma With Intramedullary Spinal and Suprasellar Metastases

Medulloblastoma is a highly aggressive embryonal tumor of the central nervous system with a strong tendency for dissemination through cerebrospinal fluid. While it occurs predominantly in pediatric populations, it is uncommon in adults. Intramedullary spinal metastases and suprasellar involvement are exceptionally rare patterns of dissemination in adults. We report the case of a 21-year-old male diagnosed with desmoplastic medulloblastoma of the cerebellar vermis who underwent ventriculoperitoneal shunting, gross total resection, and craniospinal radiotherapy. Despite receiving standard multimodal therapy, the patient developed recurrence within 12 months, presenting with rapidly progressive paraplegia and bilateral blindness. Magnetic resonance imaging (MRI) revealed tumor recurrence in the posterior fossa, suprasellar metastases involving the optic chiasm, and extensive spinal dissemination, including intramedullary and intradural metastatic lesions. This case highlights the potential for early recurrence and extensive neuroaxis dissemination in adult medulloblastoma despite initially favorable histopathology and appropriate multimodal therapy. The coexistence of intramedullary spinal metastases and suprasellar involvement represents an exceptionally rare dissemination pattern in adults, underscoring the importance of maintaining a high index of suspicion during follow-up. The development of new neurological deficits during follow-up should prompt urgent imaging of the entire neuroaxis to evaluate for metastatic dissemination. Comprehensive neuraxis surveillance and molecular characterization remain critical components in the evaluation and management of adult medulloblastoma, as they provide essential information for prognostic assessment and therapeutic decision-making.

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2024-11-12 | Differential Replication and Oncolytic Effects of Zika Virus in Aggressive CNS Tumor Cells: Insights from Organoid and Tumoroid Models

Central nervous system (CNS) cancers are responsible for high rates of morbidity and mortality worldwide. Malignant CNS tumors such as adult Glioblastoma (GBM) and pediatric embryonal CNS tumors such as medulloblastoma (MED) and atypical teratoid rhabdoid tumors (ATRT) present relevant therapeutic challenges due to the lack of response to classic treatment regimens with radio and chemotherapy. Recent findings on the Zika virus' (ZIKV) ability to infect and kill CNS neoplastic cells draw attention to the virus' oncolytic potential. Studies demonstrating the safety of using ZIKV for treating malignant CNS tumors, enabling the translation of this approach to clinical trials, are scarce in the literature. Here we developed a co-culture model of mature human cerebral organoids assembled with GBM, MED or ATRT tumor cells and used these assembloids to test ZIKV oncolytic effect, replication potential and preferential targeting between normal and cancer cells. Our hybrid co-culture models allowed the tracking of tumor cell growth and invasion in cerebral organoids. ZIKV replication and ensuing accumulation in the culture medium was higher in organoids co-cultured with tumor cells than in isolated control organoids without tumor cells. ZIKV infection led to a significant reduction in tumor cell proportion in organoids with GBM and MED cells, but not with ATRT. Tumoroids (3D cultures of tumor cells alone) were efficiently infected by ZIKV. Interestingly, ZIKV rapidly replicated in GBM, MED, and ATRT tumoroids reaching significantly higher viral RNA accumulation levels than co-cultures. Moreover, ZIKV infection reduced viable cells number in MED and ATRT tumoroids but not in GBM tumoroids. Altogether, our findings indicate that ZIKV has greater replication rates in aggressive CNS tumor cells than in normal human cells comprising cerebral organoids. However, such higher ZIKV replication in tumor cells does not necessarily parallels oncolytic effects, suggesting cellular intrinsic and extrinsic factors mediating tumor cell death by ZIKV.

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2024-02-05 | A Simple and Scalable Zebrafish Model of Sonic Hedgehog Medulloblastoma

Summary Medulloblastoma (MB) is the most common malignant brain tumor in children and is stratified into three major subgroups. The Sonic hedgehog (SHH) subgroup represents ∼30% of all MB cases and has significant survival disparity depending upon TP53 status. Here, we describe the first zebrafish model of SHH MB using CRISPR to mutate ptch1 , the primary genetic driver in human SHH MB. These tumors rapidly arise adjacent to the valvula cerebelli and resemble human SHH MB by histology and comparative genomics. In addition, ptch1- deficient MB tumors with loss of tp53 have aggressive tumor histology and significantly worse survival outcomes, comparable to human patients. The simplicity and scalability of the ptch1 MB model makes it highly amenable to CRISPR-based genome editing screens to identify genes required for SHH MB tumor formation in vivo , and here we identify the grk3 kinase as one such target.

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2023-03-31 | Data from Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET

<div>AbstractPurpose:<p>Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells.</p>Experimental Design:<p>Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed <i>in vitro</i> in a battery of CNS-PNET and AT/RT cell lines. <i>In vivo</i>, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34⁺-NSG-SGM3).</p>Results:<p>Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC₅₀ value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. <i>In vivo</i>, a single intratumoral Delta-24-RGD injection (10⁷ or 10⁸ PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD–treated tumors revealed increased CD8⁺ T-cell infiltration.</p>Conclusions:<p>Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.</p></div>

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cell therapies

2026-07-25 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial

BACKGROUND: High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. METHODS: BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. RESULTS: Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. CONCLUSIONS: Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.

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2026-06-23 | ID #989 Neurosurgical management for GD2 CAR T-cells Therapy in Pediatric and Young Adults Brain Tumors

Abstract Background Availability of fresh tumor tissue is a pre-requisite before considering GD2 CAR T treatment for patients with central nervous system tumors. Moreover, CAR T-cell therapy for central nervous system (CNS) tumors carries a relevant risk of neurotoxicity, particularly tumor inflammation–associated neurotoxicity (TIAN). We describe a monoinstitutional experience on the neurosurgical management of children and young adults treated by GD2 CAR T-cells for brain tumors. Methods Consecutive patients with relapsed/refractory CNS tumors receiving intravenous GD2-directed CAR T-cells were included in the study. Surgical biopsy was performed before treatment whenever tumoral GD2 expression was not previously available. Post-treatment biopsy was proposed in selected cases. All patients were implanted with a ventricular access device connected to a telemetric intracranical pressure (ICP) monitoring device. Results Twenty patients were included in the study. Diagnoses included embryonal tumors (n = 10), high-grade glioma (HGG; n = 4), diffuse midline glioma (DMG; n = 4), and ependymoma (n = 2). Pre-treatment biopsy was required in 10/20 patients. Post-operative biopsy was performed in 3 cases. Baseline median ICP was 6.3 cmH2O (range −5.8 to 37.4), with a median peak of 16.8 cmH2O (range 6.74–41). Median ICP variation was 11.5 points (range 5.4–30) at a median time of day 10. ICP increased after CAR-T infusion in all patients, occurring concomitantly with cytokine release syndrome. Elevations were significantly higher in patients with HGG and DMG, the only tumor types associated with TIAN. ICP changes were not correlated with severity of toxicity, but ICP did correlate with peak CAR T-cell expansion in peripheral blood and cerebrospinal fluid. No patient required an urgent invasive procedure. Conclusions neurosurgical management supports patients receiving CAR T-cells. ICP telemonitoring during GD2 CAR T-cell therapy is feasible and clinically useful. A delayed ICP peak around day 10 highlights a key monitoring window. This non-invasive approach improves safety and reduces invasive procedures.

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2026-06-23 | ID #993 Intravenous GD2 CAR T-Cell Therapy in Pediatric and Young Adult Central Nervous System Tumors: Preliminary Data

Abstract Background Immunotherapy with chimeric antigen receptor (CAR) T cells targeting the disialoganglioside GD2 may represent a therapeutic option for pediatric patients with high-grade central nervous system (CNS) tumors. Here, we report preliminary findings from an ongoing academic phase I clinical trial (NCT05298995) conducted at the Bambino Gesù Children Hospital in Rome, Italy. Methods This phase-I multi-arm, dose-escalation/descalation trial enrolled patients aged 6 months-30 years with relapsed/refractory CNS tumors to evaluate the safety/feasibility of third-generation GD2 CAR-T cells expressing an inducible caspase-9 suicide gene (GD2-CART01) intravenously administered. Five dose levels and three treatment arms were planned: Arm A (embryonal tumors), Arm B (hemispheric high-grade gliomas), and Arm C (diffuse midline gliomas and rare CNS tumors). Results Twenty-two patients have been enrolled so far; five were screening failures and 17 received GD2-CART01. Cytokine release syndrome occurred in 97% of patients. Immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 29% of patients, exclusively in Arm A, while tumor inflammation–associated neurotoxicity (TIAN) occurred in 23% and was restricted to Arms B and C. Hematologic toxicity was observed in all patients. Steroids were required in 37% of patients and AP1903 in 21%. Two dose-limiting toxicities were reported. CAR T-cell expansion was detected in all patients in blood and cerebrospinal fluid, with persistence up to 18 months post-infusion in one patient with medulloblastoma. At week 6, the disease control rate was 42% (18% partial response, 24% stable disease). Median overall survival (OS) was 6.6 months (range, 1.2–24.5), with six-month and one-year OS rates of 47% and 32.3%, respectively. The most favorable outcomes were observed in one patient with diffuse intrinsic pontine glioma alive at one year post-infusion and in three patients with medulloblastoma treated at low disease burden. Conclusions GD2-CART01 is feasible in pediatric and young adult patients with high-risk CNS tumors, with encouraging preliminary efficacy.

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2025-10-01 | P10.16.A TELEMETRIC INTRACRANIAL PRESSURE MONITORING IN PEDIATRIC AND YOUNG ADULT PATIENTS AFFECTED BY REFRACTORY AND RELAPSED BRAIN TUMORS TREATED WITH GD2 CAR T-CELLS

Abstract BACKGROUND Central nervous system (CNS) tumors represent a significant unmet medical need, characterized by high mortality and morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment option; however, patients may experience tumor inflammation-associated neurotoxicity (TIAN). TIAN can lead to pseudo-progression, resulting in increased local mass effect and intracranial hypertension. This work aims to detect early increases in intracranial pressure (ICP) in brain tumor patients treated with CAR T-cells, with the goal of improving neurological outcomes, better managing TIAN, and avoiding invasive interventions and steroid use. MATERIAL AND METHODS For all patients enrolled in the phase 1 clinical trial NCT05298995 evaluating GD2 CAR T-cells in brain tumors, a ventricular catheter connected to a Rickham reservoir and a Miethke M.scio flat telemetric ICP monitoring device will be implanted prior to the infusion. ICP will be monitored at least six times daily. Clinical data, biomarkers and kinetics of CAR T-cells will be collected during the post-infusion observation period. RESULTS Fifteen patients (6 males, 9 females; median age at diagnosis: 14.8 years) with relapsed or refractory CNS tumors were treated between December 2023 and March 2025 with GD2CAR01. Tumor types included medulloblastoma or other embryonal tumors (n=8), hemispheric high-grade gliomas (n=4), diffuse midline glioma (n=1), and ependymomas (n=2). During cytokine release syndrome, patients exhibited a median ICP increase of 9.6 cmH₂O from baseline. No severe complications related to ICP increase were reported. Clinically significant intracranial hypertension was observed in only one patient, which was effectively managed through cerebrospinal fluid aspiration via the Rickham reservoir and medical therapy. CONCLUSION This monitoring strategy is designed to provide early detection of elevated ICP levels, allowing for timely interventions such as cerebrospinal fluid drainage. The telemetric devices will facilitate continuous ICP monitoring, reduce invasiveness, improve patient comfort and safety. Implementing this strategy has the potential to enhance the safety of CAR T-cell therapy in brain tumor patients at risk of developing intracranial hypertension, ultimately improving patient outcomes. Moreover, this approach could be useful for all patients with brain tumors at risk of developing hydrocephalus.

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2025-10-01 | Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors

Background Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors. Methods Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc–/– (NSG) mouse models bearing orthotopic xenograft tumors. Results Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma. In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors. Conclusions These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.

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2024-01-19 | Radiation Therapy Plays an Important Role in the Treatment of Atypical Teratoid/Rhabdoid Tumors: Analysis of the EU-RHAB Cohorts and Their Precursors

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignancy of the central nervous system in young children with a dismal prognosis. Prognostic markers have been extensively investigated but have not been validated. The role of radiation therapy (RT) remains controversial. We evaluated the impact of RT as part of multimodality treatment by analyzing data of a European AT/RT cohort. We retrospectively analyzed data of the European Registry for Rhabdoid Tumors and its precursors. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Potential impact of prognostic factors was analyzed using univariable and multivariable Cox regression analyses with RT as a time-dependent factor. Data of 186 children (118 male, 68 female) treated from 1990 to 2016 were evaluable. The median age at diagnosis was 1.57 years (range, 0.01-26.70 years); 47% (87/186) of the patients were under the age of 18 months. Sixty-nine percent (128/186) received RT (focal RT, n = 93; craniospinal treatment with local boost, n = 34; spinal irradiation, n = 1). The median follow-up duration of the entire cohort was 1.73 years (range, 0.06-20.11 years). The estimated PFS and OS rates were 48% (95% CI, 41%-55%) and 72% (95% CI, 65%-78%) at 1 year and 33% (95% CI, 26%-40%) and 49% (95% CI, 41%-56%) at 2 years, respectively. On multivariable analysis, RT was an independent significant prognostic factor for PFS (hazard ratio, 0.45; 95% CI, 0.27-0.75; P = .002) and OS (hazard ratio, 0.54; 95% CI, 0.32-0.93; P = .025). This analysis confirms the relevance of local therapies. RT was an independent prognostic factor for outcomes in children experiencing AT/RT. However, long-term sequelae have to be carefully evaluated and considered given the young age at time of RT.

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2022-06-01 | ETMR-11. Transcriptional changes upon knockdown of alteredBCOR/BCORL1 transcripts in preclinical models of CNS embryonal tumors with BCOR-related alterations

Abstract BCL-6 transcriptional corepressor (BCOR) is an epigenetic regulator that silences gene expression mainly via the polycomb repressive complex 1.1 (PRC1.1). BCOR genomic alterations are found in a variety of different tumors and recently central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) were classified as a distinct molecular subgroup. We established and characterized two cell models derived from BCOR altered CNS tumor patients. One model is characterized by a frameshift mutation in the BCOR gene resulting in the expression of a truncated protein lacking the C-terminal PUFD domain required for correct assembly of the PRC1.1. Additionally, this model harbors a translocation of the BCOR homologue BCORL1. The second model has a characteristic internal tandem duplication (ITD) within the BCOR gene. To study the effects of mutated BCOR/BCORL1 on gene expression, we performed siRNA mediated knockdown of altered BCOR/BCORL1 transcripts in both models and analyzed transcriptional changes by mRNA expression array. Differentially expressed genes in BCOR/BCORL1 knockdown versus wild type conditions were enriched for signaling pathways involved in cell cycle progression, cell growth, DNA replication and cancer. This suggests that the alterations in BCOR/BCORL1 might have pro-oncogenic effects and thereby contribute to the aggressive phenotype of this disease. Especially in the BCOR ITD model knockdown of BCOR led to transcriptional downregulation of genes associated with the development of brain tumors such as FGF18, PDGFA and PDGFRA. Our results indicate that specific BCOR/BCORL1 alterations might impair its endogenous function as transcriptional repressor and deregulate the expression of multiple PRC1.1 target genes. An in depth characterization of epigenetic and transcriptional changes in BCOR/BCORL1 altered CNS tumors could lead to the identification of critical downstream effectors and ultimately reveal new therapeutic vulnerabilities.

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2018-06-01 | MBRS-02. PERSONALIZED IMMUNOTHERAPY WITH TRANSLATABLE RNA NANOPARTICLES TARGETING MEDULLOBLASTOMA

While recurrent medulloblastoma (MB) remains almost uniformly fatal, our group has shown a trend (p=0.07) toward improved survival in patients receiving autologous tumor-RNA pulsed dendritic cells (DCs) coupled with ex vivo expanded total RNA activated T-cells. However, the advancement of autologous cellular therapeutics remains encumbered by significant cost, complexity and time to generation. To circumvent these challenges, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA for near-immediate induction of systemic immunity against MB. We identified a clinically translatable NP formulation for the delivery of RNA to antigen presenting cells for induction of anti-tumor T-cell immunity. When administered intravenously, RNA-NPs increased expression of co-stimulatory molecules on CD11c+ cells throughout reticuloendothelial organs and within the tumor microenvironment; this phenotype was dependent on type I interferon. Targeted inhibition of type I interferon signaling (via INFAR1-mAbs) abrogated anti-tumor immunity mediated by RNA-NPs. We enhanced the immunogenicity of this platform by simply combining mRNAs encoding for immunomodulatory molecules (i.e. HCV-PAMPs, GM-CSF) or by combining RNA-NPs with immune checkpoint inhibitors. Addition of checkpoint inhibitors to RNA-NPs mediated synergistic anti-tumor activity in settings where PD-1 or PD-L1 inhibition alone did not confer therapeutic benefit. In a pre-clinical cellular immunotherapy model targeting an anaplastic murine MB, RNA NPs superseded DCs in mediating anti-tumor activity. Based on these findings, we are exploring the preclinical safety, efficacy and immunologic effects of RNA-NPs targeting malignant brain tumors in canines (UF-IACUC#:201609430) before first in-human evaluation.

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2016-04-01 | Biological basis of personalized anticoagulation in cancer: oncogene and oncomir networks as putative regulators of coagulopathy

Activation of stromal response pathways in cancer is increasingly viewed as both a local and systemic extension of molecular alterations driving malignant transformation. Rather than reflecting passive and unspecific responses to anatomical abnormalities, the coagulation system is a target of oncogenic deregulation, impacting the role of clotting and fibrinolytic proteins, and integrating hemostasis, inflammation, angiogenesis and cellular growth effects in cancer. These processes signify, but do not depend on, the clinically manifest coagulopathy and thrombosis. In this regard, the role of driver mutations affecting oncoprotein coding genes such as RAS, EGFR or MET and tumour suppressors (PTEN, TP53) are well described as regulators of tissue factor (TF), protease activated receptors (PAR-1/2) and ectopic coagulation factors (FVII). Indeed, in both adult and pediatric brain tumours the expression patterns of coagulation and angiogenesis regulators (coagulome and angiome, respectively) reflect the molecular subtypes of the underlying diseases (glioblastoma or medulloblastoma) as defined by their oncogenic classifiers and clinical course. This emerging understanding is still poorly established in relation to the transforming effects of non-coding genes, including those responsible for the expression of microRNA (miR). Indeed, several miRs have been recently found to regulate TF and other effectors. We recently documented that in the context of the aggressive embryonal tumour with multilayered rosettes (ETMR) the oncogenic driver miR (miR-520 g) suppresses the expression of TF and correlates with hypocoagulant tumour characteristics. Unlike in adult cancers, the growth of pediatric embryonal brain tumour cells as spheres (to maintain stem cell properties) results in upregulation of miR-520 g and downregulation of TF expression and activity. We postulate that oncogenic protein and miR coding genes form alternative pathways of coagulation system regulation in different tumour settings, a property necessitating more personalised and biologically-based approaches to anticoagulation.

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2012-05-06 | Exosome-delivered microRNAs of “chromosome 19 microRNA cluster” as immunomodulators in pregnancy and tumorigenesis

Structural rearrangements of chromosomal band 19q13 are a non-random cytogenetic abnormality in thyroid adenomas and adenomatous goiters and lead to an expression of miRNAs of the chromosome 19 microRNA cluster C19MC. Normally, expression of these miRNAs is silenced except for embryonic stem cells and the placenta where they represent the majority of miRNAs not only in the trophoblast but also in exosomes derived from it. We have advanced the hypothesis that as part of the feto-maternal communication miRNAs of C19MC serve immunomodulatory functions in the placenta and confer a growth advantage to thyroid nodules by protecting them against autoimmune attacks. More precisely, the exosomes containing these miRNAs may specifically target immune cells in their local environment as well as systemically by transferring their cargo to recipient cells. Within these target cells the transferred miRNAs can interact with mRNAs of the recipient cells thereby suppressing their immune-specific functions. Experiments used to demonstrate the immunomodulatory capacity of placenta-derived exosomes can be modified by transfecting the target cells with those miRNAs of C19MC represented in placental exosomes. Mimics of C19MC-derived miRNAs might develop to useful drug candidates for the treatment of autoimmune disease as e.g. rheumatoid arthritis and Sjögren's syndrome and for the prevention of transplant rejection. In case of tumor entities with elevated expression of C19MC miRNAs these miRNAs may be interesting targets for treatment with appropriate antagonists.

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