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Phase I study of anti-GD2 Chimeric Antigen Receptor-Expressing T cells in pediatric and young adult patients affected by relapsed/refractory central nervous system tumors: preliminary data
Full text linkIntroduction: Despite the use of aggressive multimodal treatments, childhood central nervous system (CNS) tumors remain a major cause of morbidity and mortality among pediatric patients. Chimeric antigen receptor (CAR) T-cell therapies have emerged as promising options. Here, we present preliminary data of a Phase 1 clinical trial to evaluate GD2-targeting CAR T-cells (GD2-CART01) for treating recurrent or refractory CNS tumors in pediatric and young adult patients.
Materials and methods: This trial is designed to stratify patients into three arms based on tumor histology and location to sequentially evaluate safety: ARM A (medulloblastoma and other embryonal tumors), ARM B (hemispheric high-grade gliomas), and ARM C (thalamic HGG, diffuse midline glioma, DIPG, and other rare CNS tumors). Each arm follows a 3+3 dose escalation/de-escalation schema across five dose levels (DL): DL1 (0.25 x 10^6 cells/kg), DL2 (0.5 x 10^6 cells/kg), DL3 (1.0 x 10^6 cells/kg), DL4 (3.0 x 10^6 cells/kg), and DL5 (6.0 x 10^6 cells/kg). The treatment plan will include: T-cell apheresis, retroviral production, T-cell production and transduction, lymphodepleting regimen and iC9-GD2-CAR-T cell infusion. Patients will be monitored clinically, with laboratory tests, and by detecting CAR and cytokines in cerebrospinal fluid (CSF) and blood. Brain and spine magnetic resonance imaging (MRI) and CSF cytology will be used to assess disease response.
Results: Between November 2023 and October 2024, 12 patients were enrolled, with 8 receiving treatment. GD2-CART01 was manufactured successfully in all the patients. All treated patients demonstrated CAR T-cell expansion, peaking around two weeks post-infusion. There was no significant difference in CAR T expansion and cytokine levels between the two different dose levels tested, nor between arms of treatment. However, it appears that the patients in arm B had greater CAR T expansion and cytokine expression. No dose-limiting toxic effects were reported in patients treated to date. Mild cytokine release syndrome occurred in 87.5% of cases, correlating with elevated cytokine levels in both PB and CSF. Two patients (25%) experienced Immune effector cell-associated neurotoxicity syndrome. Tumor inflammation associated neurotoxicity was reported in two cases (25%). All patients underwent intracranial pressure (ICP) telemetric monitoring, and none experienced complications related to intracranial hypertension. Hematologic toxic effects developed in all the patients. All side effects were reversible. Regarding patient outcomes at six week post infusion, we documented one partial response, three disease progression, one case of pseudoprogression, and one stable disease.
Conclusions: Our initial findings suggest that GD2 CAR T-cell therapy is safe. In terms of kinetics, we observed CAR T-cell expansion and cytokine increases in all cases. However, a single systemic infusion may not suffice to control the disease, highlighting the need to explore additional intraventricular infusions. Patient selection also appears crucial, as lower tumor burden may enhance treatment efficacy
2. Genetic prothrombotic factors in children with otogenic lateral sinus thrombosis: five case reports
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Genetic prothrombotic factors in children with otogenic lateral sinus thrombosis: five case reports
Author(s): Zangari, P (Zangari, Paola)1; Messia, V (Messia, Virginia)1; Viccaro, M (Viccaro, Marika)2; Bottero, S (Bottero, Sergio)2; Randisi, F (Randisi, Francesco)3; Marsella, P (Marsella, Pasquale)2; Luciani, M (Luciani, Matteo)4; Locatelli, F (Locatelli, Franco)4
Source: BLOOD COAGULATION & FIBRINOLYSIS Volume: 23 Issue: 2 Pages: 158-163 DOI: 10.1097/MBC.0b013e328349cafb Published: MAR 2012
Times Cited: 0 (from Web of Science)
Cited References: 20 [ view related records ] Citation Map
Abstract: Lateral sinus thrombosis (LST) is an uncommon, but life-threatening complication of both acute and chronic otitis media. There is some evidence that acquired or hereditary prothrombotic disorders are risk factors for LST. The aim of this work was to evaluate the role of thrombotic screening, anticoagulant therapy or prophylaxis in patients with either acute or chronic otitis media and LST. The medical records of five children hospitalized at Pediatric Hospital Bambino Gesu of Rome because of acute or chronic otitis media complicated by mastoiditis and LST were reviewed. All children underwent laboratory workup for hypercoagulability. All the five children were found to be heterozygote for the C677T MTHFR mutation and a child presented also heterozygosity for factor V Leiden mutation. They have been successfully treated with anticoagulant therapy without sequels. Children with acute or chronic otitis media may have a prothrombotic tendency that becomes clinically evident because of the inflammatory state. Patients with a family and/or personal history of thrombosis and/or thrombophilic conditions need anticoagulant prophylaxis also in the absence of clear signs of LST. Treatment with low molecular weight is successful in patients with LST. Blood Coagul Fibrinolysis 23:158-163 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
The role of repeat transplantation of haemopoietic stem cells and adoptive immunotherapy in treatment of leukemia relapsing following allogeneic transplantation
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Overexpression of Osmyb4 enhances compatible solute accumulation and increases stress tolerance of arabidopsis thaliana
No full textIn this paper, we report the metabolic and molecular changes in response to cold and drought induced in Osmyb4 transgenic Arabidopsis thaliana compared with the wildtype (WT). The rice Osmyb4 gene codes for a transcription factor (Myb4) induced by cold treatment and, in Arabidopsis transgenic plants, improves cold and freezing tolerance [Vannini C, Locatelli F, Bracale M, Magnani E, Marsoni M, Osnato M, Mattana M, Baldoni E, Coraggio I (2004) Plant J 37: 115-127]. Here, we report the ability of Myb4 to induce also drought tolerance in Arabidopsis transgenic plants. By the use of nuclear magnetic resonance (NMR) and enzymatic assays, we showed that several compatible solutes (glucose, fructose, sucrose, proline, glycine betaine and sinapoyl malate) accumulate in higher amount in Osmyb4-overexpressing plants with respect to the WT, both under normal and stress conditions. Considering proline, we also found that in transgenic plants the levels of the mRNAs coding for Δ1- pyrroline-5-carboxylate synthase (EC not assigned) and for Δ1- pyrroline-5-carboxylate dehydrogenase (EC 1.5.1.12) were higher and lower, respectively. The constitutive activation of several stress-inducible pathways and different kinetics in the accumulation of several metabolites, in Myb4 transgenic plants, may represent an advantage to prepare plants to face the stress condition. Moreover, these results taken together suggest that Myb4 integrates the activation of multiple components of stress response
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Strategies to harness immunity against infectious pathogens after haploidentical stem cell transplantation
No full textViral and fungal infections account for significant morbidity and mortality, particularly in pediatric patients with profound immune suppression resulting from allogeneic hematopoietic stem cell transplantation (HSCT). Therapies with anti-viral and anti-fungal drugs are often associated with significant toxicity, are of limited efficacy and can induce drug resistance. One innovative approach to prevent and/or treat viral and fungal infections involves the adoptive transfer of in vitro-expanded or in vitro-generated pathogen-specific T cells. This review summarizes the clinical trials that have been run to date with virus- and fungus-specific T cells, with special emphasis on the clinical context of haploidentical HSCT for pediatric malignancies. It will also discuss initiatives and strategies to overcome the hurdles associated with time-consuming and complex GMP-grade laboratory procedures required to generate pathogen-specific T cells
Tolerance: pregnancy matters
No full textIn this issue of Blood, van Halteren and colleagues demonstrate that not only antigen-specific CD8 + CTLs, but also antigen-specific CD8 + T regs can emerge during pregnancy and persist over time when mother and offspring differ for minor histocompatibility antigens.1 The relative ratio between these 2 populations, either promoting aggression against allogeneic tissues or tumor cells or tolerance toward alloantigens, is of potential great relevance in the context of HSCT
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