RESUMO
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Gangliosídeos , Glioma , Histonas , Imunoterapia Adotiva , Mutação , Receptores de Antígenos Quiméricos , Astrocitoma/genética , Astrocitoma/imunologia , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Criança , Gangliosídeos/imunologia , Perfilação da Expressão Gênica , Glioma/genética , Glioma/imunologia , Glioma/patologia , Glioma/terapia , Histonas/genética , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/imunologia , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/terapiaRESUMO
A common complication of chimeric antigen receptor (CAR) T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS), which presents with encephalopathy, aphasia, inattention, somnolence, seizures, weakness, or cerebral edema. Despite its significant morbidity, there are currently no effective targeted treatments. Given the clinical similarities between ICANS and the neurological manifestations of acute hypophosphatemia, we retrospectively reviewed 499 patients treated with CD19-targeted CAR T-cell therapy across multiple clinical trials between 2015 and 2020. In addition to clinical toxicities experienced by the patients, we also interrogated the impact of serum electrolyte data and repletion of corresponding electrolyte deficiencies with ICANS incidence, severity, and duration. Hypophosphatemia was a common occurrence in CAR T-cell recipients and the only electrolyte derangement associated with a significantly higher cumulative incidence of ICANS. Moreover, phosphorus repletion in patients with hypophosphatemia was associated with significantly decreased ICANS incidence and duration. Hypophosphatemia was uniquely associated with encephalopathy neurological adverse events, which also showed the strongest positive correlation with both ICANS and cytokine release syndrome severity. These findings suggest that serum phosphorus could be a reliable biomarker for ICANS, and expeditious, goal-directed phosphorus repletion in response to serum hypophosphatemia could be a safe, inexpensive, and widely available intervention for such patients. SIGNIFICANCE: Herein we show that phosphorus repletion in patients with hypophosphatemia receiving anti-CD19 chimeric antigen receptor T-cell therapeutics was associated with significantly decreased immune effector cell-associated neurotoxicity syndrome (ICANS) incidence and symptom duration. Given the significant morbidity associated with ICANS and lack of targeted interventions, hypophosphatemia may serve as both a useful biomarker and an inexpensive intervention for ICANS.
Assuntos
Hipofosfatemia , Imunoterapia Adotiva , Síndromes Neurotóxicas , Humanos , Hipofosfatemia/epidemiologia , Hipofosfatemia/terapia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Estudos Retrospectivos , Incidência , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/imunologia , Pessoa de Meia-Idade , Adulto , Idoso , Ensaios Clínicos como Assunto , Adulto Jovem , Receptores de Antígenos Quiméricos/imunologia , AdolescenteRESUMO
ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.
Assuntos
Linfoma de Célula do Manto , Síndromes Neurotóxicas , Humanos , Adulto , Linfoma de Célula do Manto/terapia , Imunoterapia Adotiva/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19 , Encéfalo , Síndrome da Liberação de CitocinaRESUMO
Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, ß-, and γ-synuclein. α-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized αßγ-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by â¼30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease.
Assuntos
Neurônios/fisiologia , Sinapses/patologia , Transmissão Sináptica/genética , Sinucleínas/genética , Sinucleínas/fisiologia , Fatores Etários , Animais , Deleção de Genes , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/análise , Doença de Parkinson/etiologia , Fenótipo , Sinucleínas/deficiência , alfa-Sinucleína/deficiência , alfa-Sinucleína/genética , beta-Sinucleína/deficiência , beta-Sinucleína/genética , gama-Sinucleína/deficiência , gama-Sinucleína/genéticaRESUMO
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.
Assuntos
Leucoencefalopatia Multifocal Progressiva , Linfoma de Célula do Manto , Síndromes Neurotóxicas , Receptores de Antígenos Quiméricos , Animais , Imunoterapia Adotiva , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia , Proteínas Adaptadoras de Transdução de SinalRESUMO
Stroke is the leading cause of adult disability. Yet there is a limited degree of recovery in this disease. One of the mechanisms of recovery is the formation of new connections in the brain and spinal cord after stroke: post-stroke axonal sprouting. Studies indicate that post-stroke axonal sprouting occurs in mice, rats, primates and humans. Inducing post-stroke axonal sprouting in specific connections enhances recovery; blocking axonal sprouting impairs recovery. Behavioral activity patterns after stroke modify the axonal sprouting response. A unique regenerative molecular program mediates this aspect of tissue repair in the CNS. The types of connections that are formed after stroke indicate three patterns of axonal sprouting after stroke: reactive, reparative and unbounded axonal sprouting. These differ in mechanism, location, relationship to behavioral recovery and, importantly, in their prospect for therapeutic manipulation to enhance tissue repair.
Assuntos
Axônios/fisiologia , Regeneração Nervosa/genética , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Axônios/patologia , Humanos , Plasticidade Neuronal/fisiologia , Neurônios/patologia , Recuperação de Função Fisiológica/fisiologiaRESUMO
Stroke produces a limited process of neural repair. Axonal sprouting in cortex adjacent to the infarct is part of this recovery process, but the signal that initiates axonal sprouting is not known. Growth and differentiation factor 10 (GDF10) is induced in peri-infarct neurons in mice, non-human primates and humans. GDF10 promotes axonal outgrowth in vitro in mouse, rat and human neurons through TGFßRI and TGFßRII signaling. Using pharmacogenetic gain- and loss-of-function studies, we found that GDF10 produced axonal sprouting and enhanced functional recovery after stroke; knocking down GDF10 blocked axonal sprouting and reduced recovery. RNA sequencing from peri-infarct cortical neurons revealed that GDF10 downregulated PTEN, upregulated PI3 kinase signaling and induced specific axonal guidance molecules. Using unsupervised genome-wide association analysis of the GDF10 transcriptome, we found that it was not related to neurodevelopment, but may partially overlap with other CNS injury patterns. Thus, GDF10 is a stroke-induced signal for axonal sprouting and functional recovery.