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H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.
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All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
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Analgésicos Opioides , Bainha de Mielina , Vias Neurais , Plasticidade Neuronal , Recompensa , Área Tegmentar Ventral , Animais , Feminino , Masculino , Camundongos , Analgésicos Opioides/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfina/farmacologia , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Optogenética , Área Tegmentar Ventral/fisiologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Linhagem da CélulaRESUMO
Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is limited. We present an epigenetically defined neural signature of glioblastoma that independently predicts patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals a high abundance of malignant stemcell-like cells in high-neural glioblastoma, primarily of the neural lineage. These cells are further classified as neural-progenitor-cell-like, astrocyte-like and oligodendrocyte-progenitor-like, alongside oligodendrocytes and excitatory neurons. In line with these findings, high-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature is associated with decreased overall and progression-free survival. High-neural tumors also exhibit increased functional connectivity in magnetencephalography and resting-state magnet resonance imaging and can be detected via DNA analytes and brain-derived neurotrophic factor in patients' plasma. The prognostic importance of the neural signature was further validated in patients diagnosed with diffuse midline glioma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant. High-neural gliomas likely require a maximized surgical resection approach for improved outcomes.
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Neoplasias Encefálicas , Epigênese Genética , Glioma , Humanos , Prognóstico , Glioma/genética , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA/genética , Animais , Camundongos , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Pessoa de Meia-Idade , Neurônios/patologia , Neurônios/metabolismo , Adulto , Análise de Célula Única , Linhagem Celular Tumoral , Transcriptoma , Gradação de TumoresRESUMO
Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
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Antígeno CD47 , Imunoterapia Adotiva , Neoplasias , Linfócitos T , Animais , Feminino , Humanos , Masculino , Camundongos , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Antígeno CD47/genética , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Imunoterapia Adotiva/métodos , Macrófagos/citologia , Macrófagos/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Microambiente Tumoral/imunologia , Anticorpos/imunologia , Anticorpos/uso terapêutico , Ativação de MacrófagosRESUMO
High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.
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Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.
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Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Glioma/fisiopatologia , Glioma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatologia , Prognóstico , Criança , Isocitrato Desidrogenase/genética , MutaçãoRESUMO
Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Microglial depletion rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.
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Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.
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Aprendizagem , Neurofibromina 1 , Plasticidade Neuronal , Oligodendroglia , Animais , Camundongos , Oligodendroglia/metabolismo , Masculino , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Plasticidade Neuronal/genética , Feminino , Neurofibromina 1/genética , Mutação , Atividade Motora/fisiologia , Atividade Motora/genética , Diferenciação Celular/fisiologia , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.
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Neoplasias , Neurociências , Humanos , Sistema Nervoso Central , Previsões , ProteômicaRESUMO
SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.
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Neoplasias , Humanos , Neoplasias/genéticaRESUMO
Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.
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Síndrome do Desconforto Respiratório , Sobreviventes , Humanos , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/fisiopatologia , Estados Unidos , National Heart, Lung, and Blood Institute (U.S.) , Qualidade de Vida , Encéfalo/fisiopatologiaRESUMO
The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
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Adaptação Fisiológica , Glioma , Plasticidade Neuronal , Sinapses , Animais , Criança , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proliferação de Células , Progressão da Doença , Glioma/metabolismo , Glioma/patologia , Ácido Glutâmico/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de AMPA/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Microambiente Tumoral , OptogenéticaRESUMO
Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.
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Glioma , Neurônios , Humanos , Neurônios/fisiologia , Oligodendroglia/fisiologia , Bainha de Mielina/fisiologia , Neuroglia/fisiologiaRESUMO
Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.
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Anticorpos Antivirais , Herpesvirus Humano 4 , Hidrocortisona , Linfócitos , Células Mieloides , Síndrome de COVID-19 Pós-Aguda , SARS-CoV-2 , Humanos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Biomarcadores/sangue , Estudos Transversais , Herpesvirus Humano 4/imunologia , Hidrocortisona/sangue , Imunofenotipagem , Linfócitos/imunologia , Aprendizado de Máquina , Células Mieloides/imunologia , Síndrome de COVID-19 Pós-Aguda/diagnóstico , Síndrome de COVID-19 Pós-Aguda/imunologia , Síndrome de COVID-19 Pós-Aguda/fisiopatologia , Síndrome de COVID-19 Pós-Aguda/virologia , SARS-CoV-2/imunologiaRESUMO
Introduction: Diffuse intrinsic pontine glioma (DIPG), recently reclassified as a subtype of diffuse midline glioma, is a highly aggressive brainstem tumor affecting children and young adults, with no cure and a median survival of only 9 months. Conventional treatments are ineffective, highlighting the need for alternative therapeutic strategies such as cellular immunotherapy. However, identifying unique and tumor-specific cell surface antigens to target with chimeric antigen receptor (CAR) or T-cell receptor (TCR) therapies is challenging. Methods: In this study, a multi-omics approach was used to interrogate patient-derived DIPG cell lines and to identify potential targets for immunotherapy. Results: Through immunopeptidomics, a range of targetable peptide antigens from cancer testis and tumor-associated antigens as well as peptides derived from human endogenous retroviral elements were identified. Proteomics analysis also revealed upregulation of potential drug targets and cell surface proteins such as Cluster of differentiation 27 (CD276) B7 homolog 3 protein (B7H3), Interleukin 13 alpha receptor 2 (IL-13Rα2), Human Epidermal Growth Factor Receptor 3 (HER2), Ephrin Type-A Receptor 2 (EphA2), and Ephrin Type-A Receptor 3 (EphA3). Discussion: The results of this study provide a valuable resource for the scientific community to accelerate immunotherapeutic approaches for DIPG. Identifying potential targets for CAR and TCR therapies could open up new avenues for treating this devastating disease.
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Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.
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BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG. PATIENTS AND METHODS: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose. RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT. CONCLUSIONS: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.
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Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Neutropenia , Síndrome da Leucoencefalopatia Posterior , Trombocitopenia , Criança , Humanos , Panobinostat/farmacocinética , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Glioma/tratamento farmacológico , Glioma/patologia , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/patologiaRESUMO
Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules. Because survival statistics have been stagnant for many decades, and therapies targeting the unique biology of DMG are urgently needed, this has prompted the clinical assessment of chimeric antigen receptor (CAR) T cell therapies in this setting. We highlight the current landscape of CAR T cell therapy for DMG, the role the TIME may play in the response, and strategies to overcome treatment obstacles.
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Glioma , Imunoterapia Adotiva , Criança , Humanos , Sistema Nervoso Central , Microambiente Tumoral , Glioma/genética , Glioma/terapiaRESUMO
Brain metastases cause cognitive impairment and impair quality of life. Sanchez-Aguilera et al. examine the effects of metastases on brain function leveraging in vivo electrocorticography and machine learning to reveal tumor model-specific changes in neural circuit dynamics and find that the electrophysiological profile predicts the presence and type of brain metastasis.
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Neoplasias Encefálicas , Qualidade de Vida , Humanos , Aprendizado de MáquinaRESUMO
The nervous system regulates tissue stem and precursor populations throughout life. Parallel to roles in development, the nervous system is emerging as a critical regulator of cancer, from oncogenesis to malignant growth and metastatic spread. Various preclinical models in a range of malignancies have demonstrated that nervous system activity can control cancer initiation and powerfully influence cancer progression and metastasis. Just as the nervous system can regulate cancer progression, cancer also remodels and hijacks nervous system structure and function. Interactions between the nervous system and cancer occur both in the local tumour microenvironment and systemically. Neurons and glial cells communicate directly with malignant cells in the tumour microenvironment through paracrine factors and, in some cases, through neuron-to-cancer cell synapses. Additionally, indirect interactions occur at a distance through circulating signals and through influences on immune cell trafficking and function. Such cross-talk among the nervous system, immune system and cancer-both systemically and in the local tumour microenvironment-regulates pro-tumour inflammation and anti-cancer immunity. Elucidating the neuroscience of cancer, which calls for interdisciplinary collaboration among the fields of neuroscience, developmental biology, immunology and cancer biology, may advance effective therapies for many of the most difficult to treat malignancies.