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1.
Cell ; 187(10): 2485-2501.e26, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38653236

RESUMO

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioblastoma/patologia , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Análise Espacial , Transcriptoma/genética , Microambiente Tumoral , Proteômica , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Regulação Neoplásica da Expressão Gênica
2.
Cell ; 161(4): 803-16, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25913192

RESUMO

Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.


Assuntos
Neoplasias Encefálicas/patologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proliferação de Células , Glioma/patologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Sequência de Aminoácidos , Animais , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Transplante de Neoplasias , Neurônios/metabolismo
3.
Nature ; 630(8016): 457-465, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38750365

RESUMO

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.


Assuntos
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 Macrófagos
4.
Nature ; 603(7903): 934-941, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35130560

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/terapia
5.
N Engl J Med ; 390(14): 1290-1298, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38477966

RESUMO

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).


Assuntos
Receptores ErbB , Glioblastoma , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Humanos , Linfócitos T CD8-Positivos/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/terapia , Glioblastoma/patologia , Imunoterapia Adotiva/efeitos adversos , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico
7.
Nat Neurosci ; 27(8): 1555-1564, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38816530

RESUMO

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.


Assuntos
Aprendizagem , Neurofibromina 1 , Plasticidade Neuronal , Oligodendroglia , Animais , Feminino , Masculino , Camundongos , Diferenciação Celular/fisiologia , Aprendizagem/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Atividade Motora/genética , Mutação , Neurofibromina 1/genética , Plasticidade Neuronal/fisiologia , Plasticidade Neuronal/genética , Oligodendroglia/metabolismo
8.
Nat Commun ; 14(1): 7509, 2023 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-37980341

RESUMO

Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.


Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/metabolismo , Imunoterapia Adotiva , Antígeno de Maturação de Linfócitos B/genética , Linfócitos T
9.
Mol Pharm ; 9(1): 135-43, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22118658

RESUMO

Polymeric micelles formed by the self-assembly of amphiphilic block copolymers can be used to encapsulate hydrophobic drugs for tumor-delivery applications. Filamentous carriers with high aspect ratios offer potential advantages over spherical carriers, including prolonged circulation times. In this work, mixed micelles composed of poly(ethylene oxide)-poly[(R)-3-hydroxybutyrate]-poly(ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127 (PF-127) were used to encapsulate a near-infrared fluorophore. The micelle formulations were assessed for tumor accumulation after tail vein injection to xenograft tumor-bearing mice by noninvasive optical imaging. The mixed micelle formulation that facilitated the highest tumor accumulation was shown by cryo-electron microscopy to be filamentous in structure compared to spherical structures of pure PF-127 micelles. In addition, increased dye loading efficiency and dye stability were attained in this mixed micelle formulation compared to pure PEO-PHB-PEO micelles. Therefore, the optimized PEO-PHB-PEO/PF-127 mixed micelle formulation offers advantages for cancer delivery over micelles formed from the individual copolymer components.


Assuntos
Meios de Contraste/administração & dosagem , Portadores de Fármacos/administração & dosagem , Verde de Indocianina/administração & dosagem , Melanoma Experimental/diagnóstico , Poloxâmero/química , Polietilenoglicóis/química , Animais , Fenômenos Químicos , Meios de Contraste/análise , Meios de Contraste/farmacocinética , Portadores de Fármacos/análise , Portadores de Fármacos/farmacocinética , Composição de Medicamentos , Estabilidade de Medicamentos , Humanos , Verde de Indocianina/análise , Verde de Indocianina/farmacocinética , Injeções Intravenosas , Masculino , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Proibitinas , Organismos Livres de Patógenos Específicos , Espectroscopia de Luz Próxima ao Infravermelho , Distribuição Tecidual , Imagem Corporal Total
10.
Antibodies (Basel) ; 11(2)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35645204

RESUMO

Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient's own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.

11.
Pharm Res ; 27(9): 1900-13, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20568000

RESUMO

PURPOSE: Indocyanine green (ICG), an FDA-approved near infrared (NIR) dye, has potential application as a contrast agent for tumor detection. Because ICG binds strongly to plasma proteins and exhibits aqueous, photo, and thermal instability, its current applications are largely limited to monitoring blood flow. To address these issues, ICG was encapsulated and stabilized within polymeric micelles formed from the thermo-sensitive block copolymer Pluronic F-127, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), to increase the stability and circulation time of ICG. METHODS: ICG-loaded Pluronic micelles were prepared at various concentrations of Pluronic and ICG and characterized by determining particle sizes, dye loading efficiency, and the kinetics of dye degradation. Förster resonance energy transfer spectroscopy was employed to monitor the stability of Pluronic micelles in physiological solutions. The plasma clearance kinetics and biodistribution of ICG-loaded micelles was also determined after intravenous delivery to CT-26 colon carcinoma tumor-bearing mice, and NIR whole-body imaging was performed for tumor detection. RESULTS: The Pluronic F-127 micelles showed efficient ICG loading, small size, stabilized ICG fluorescence, and prolonged circulation in vivo. Solid tumors in mice were specifically visualized after intravenous administration of ICG-loaded micelles. CONCLUSIONS: These materials are therefore promising formulations for noninvasive NIR tumor imaging applications.


Assuntos
Meios de Contraste/química , Portadores de Fármacos/química , Verde de Indocianina/química , Neoplasias/diagnóstico , Poloxâmero/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Animais , Meios de Contraste/farmacocinética , Proteínas de Drosophila , Estabilidade de Medicamentos , Feminino , Transferência Ressonante de Energia de Fluorescência , Verde de Indocianina/farmacocinética , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Tamanho da Partícula , Temperatura
12.
Nat Med ; 26(5): 712-719, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341579

RESUMO

Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.


Assuntos
Antígenos B7/imunologia , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adulto , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Células Cultivadas , Pré-Escolar , Feminino , Feto/patologia , Humanos , Lactente , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tumor Rabdoide/imunologia , Tumor Rabdoide/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Teratoma/imunologia , Teratoma/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Elife ; 82019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625910

RESUMO

Neurons form bona fide synapses with oligodendrocyte precursor cells (OPCs), but the circuit context of these neuron to OPC synapses remains incompletely understood. Using monosynaptically-restricted rabies virus tracing of OPC afferents, we identified extensive afferent synaptic inputs to OPCs residing in secondary motor cortex, corpus callosum, and primary somatosensory cortex of adult mice. These inputs primarily arise from functionally-interconnecting cortical areas and thalamic nuclei, illustrating that OPCs have strikingly comprehensive synaptic access to brain-wide projection networks. Quantification of these inputs revealed excitatory and inhibitory components that are consistent in number across brain regions and stable in barrel cortex despite whisker trimming-induced sensory deprivation.


Assuntos
Vias Aferentes/anatomia & histologia , Corpo Caloso/anatomia & histologia , Córtex Motor/anatomia & histologia , Técnicas de Rastreamento Neuroanatômico , Neurônios/fisiologia , Células Precursoras de Oligodendrócitos/fisiologia , Córtex Somatossensorial/anatomia & histologia , Vias Aferentes/fisiologia , Animais , Corpo Caloso/fisiologia , Camundongos , Córtex Motor/fisiologia , Córtex Somatossensorial/fisiologia
14.
Clin Cancer Res ; 25(8): 2560-2574, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30655315

RESUMO

PURPOSE: Patients with relapsed pediatric solid tumors and CNS malignancies have few therapeutic options and frequently die of their disease. Chimeric antigen receptor (CAR) T cells have shown tremendous success in treating relapsed pediatric acute lymphoblastic leukemia, but this has not yet translated to treating solid tumors. This is partially due to a paucity of differentially expressed cell surface molecules on solid tumors that can be safely targeted. Here, we present B7-H3 (CD276) as a putative target for CAR T-cell therapy of pediatric solid tumors, including those arising in the central nervous system. EXPERIMENTAL DESIGN: We developed a novel B7-H3 CAR whose binder is derived from a mAb that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials. We tested B7-H3 CAR T cells in a variety of pediatric cancer models. RESULTS: B7-H3 CAR T cells mediate significant antitumor activity in vivo, causing regression of established solid tumors in xenograft models including osteosarcoma, medulloblastoma, and Ewing sarcoma. We demonstrate that B7-H3 CAR T-cell efficacy is largely dependent upon high surface target antigen density on tumor tissues and that activity is greatly diminished against target cells that express low levels of antigen, thus providing a possible therapeutic window despite low-level normal tissue expression of B7-H3. CONCLUSIONS: B7-H3 CAR T cells could represent an exciting therapeutic option for patients with certain lethal relapsed or refractory pediatric malignancies, and should be tested in carefully designed clinical trials.


Assuntos
Antígenos de Neoplasias/imunologia , Antígenos B7/imunologia , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/metabolismo , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Antígenos B7/antagonistas & inibidores , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Imunoterapia Adotiva/métodos , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Med ; 24(5): 572-579, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662203

RESUMO

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.


Assuntos
Neoplasias Encefálicas/imunologia , Gangliosídeos/metabolismo , Glioma/imunologia , Histonas/metabolismo , Imunoterapia Adotiva , Lisina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Humanos , Metilação , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Neuron ; 95(4): 743-756, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28817797

RESUMO

Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and functional connectivity of neurons have been appreciated since the classic work of Hubel and Wiesel (1963; Wiesel and Hubel, 1963a, 1963b). In recent years, a similar structural plasticity has come to light for the myelinated infrastructure of the nervous system. While an innate program of myelin development proceeds independently of nervous system activity, increasing evidence supports a role for activity-dependent, plastic changes in myelin-forming cells that influence myelin structure and neurological function. Accumulating evidence of complementary and likely temporally overlapping activity-independent and activity-dependent modes of myelination are beginning to crystallize in a model of myelin plasticity, with broad implications for neurological function in health and disease.


Assuntos
Adaptação Fisiológica/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Bainha de Mielina/fisiologia , Neuroglia/fisiologia , Neurônios/fisiologia , Sinais (Psicologia) , Neurotransmissores/metabolismo
17.
Biomaterials ; 35(31): 8895-8902, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25064804

RESUMO

Components of the blood have been proposed as potential therapeutic targets for improving cellular regeneration after injury and neurodegenerative disease. In this work, thrombin is shown to increase endogenous neural progenitor proliferation in the intact murine spinal cord. A local injection of heparin before a spinal cord injury reduces cell proliferation and astrogliogenesis associated with scarring. We sought to create depot-formulations of PLGA microsphere and Pluronic F-127 for sustained local delivery of two thrombin inhibitors, heparin and hirudin. Each hydrogel depot-formulation showed delayed drug release compared to microspheres or hydrogel alone. Animals with a lateral demyelination lesion showed a reduction in CD68+ macrophages when treated with hirudin-loaded PLGA/F-127 gels compared to control and heparin-treated animals. Moreover, hirudin-loaded materials showed an accelerated recovery in coordinated stepping and increased oligodendrocyte densities. Together, these data demonstrate that controlled delivery of hirudin accelerates functional recovery from a demyelination lesion in the spinal cord.


Assuntos
Antitrombinas/administração & dosagem , Preparações de Ação Retardada/química , Doenças Desmielinizantes/tratamento farmacológico , Hirudinas/administração & dosagem , Ácido Láctico/química , Poloxâmero/química , Ácido Poliglicólico/química , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Antitrombinas/uso terapêutico , Doenças Desmielinizantes/patologia , Doenças Desmielinizantes/fisiopatologia , Fibrinolíticos/administração & dosagem , Fibrinolíticos/uso terapêutico , Heparina/administração & dosagem , Heparina/uso terapêutico , Terapia com Hirudina , Camundongos , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
18.
Science ; 344(6183): 1252304, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24727982

RESUMO

Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.


Assuntos
Diferenciação Celular , Córtex Motor/fisiologia , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Oligodendroglia/citologia , Animais , Comportamento Animal/fisiologia , Linhagem da Célula , Proliferação de Células , Channelrhodopsins , Corpo Caloso/citologia , Corpo Caloso/fisiologia , Camundongos , Camundongos Mutantes , Atividade Motora/fisiologia , Córtex Motor/citologia , Antígenos Thy-1/genética
19.
Biomaterials ; 34(18): 4501-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23498892

RESUMO

Polymeric micelles are promising carriers for anti-cancer agents due to their small size, ease of assembly, and versatility for functionalization. A current challenge in the use of polymeric micelles is the sensitive balance that must be achieved between stability during prolonged blood circulation and release of active drug at the tumor site. Stimuli-responsive materials provide a mechanism for triggered drug release in the acidic tumor and intracellular microenvironments. In this work, we synthesized a series of dual pH- and temperature-responsive block copolymers containing a poly(ε-caprolactone) (PCL) hydrophobic block with a poly(triethylene glycol) block that were copolymerized with an amino acid-functionalized monomer. The block copolymers formed micellar structures in aqueous solutions. An optimized polymer that was functionalized with 6-aminocaproic acid (ACA) possessed pH-sensitive phase transitions at mildly acidic pH and body temperature. Doxorubicin-loaded micelles formed from these polymers were stable at blood pH (~7.4) and showed increased drug release at acidic pH. In addition, these micelles displayed more potent anti-cancer activity than free doxorubicin when tested in a tumor xenograft model in mice.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Polímeros/síntese química , Temperatura , Ácido Aminocaproico/síntese química , Ácido Aminocaproico/química , Animais , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Injeções , Cinética , Luz , Masculino , Camundongos , Camundongos Nus , Micelas , Nanopartículas/ultraestrutura , Neoplasias/patologia , Tamanho da Partícula , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polímeros/química , Espalhamento de Radiação , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biomaterials ; 31(28): 7386-97, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20598741

RESUMO

Doxorubicin (DOX) is an effective chemotherapeutic against a wide range of solid tumors. However, its clinical use is limited by severe side effects such as cardiotoxicity as well as inherent and acquired drug resistance of tumors. DOX encapsulation within self-assembled polymeric micelles has the potential to decrease the systemic distribution of free drug and enhance the drug accumulation in the tumor via the enhanced permeability and retention (EPR). In this study, DOX was encapsulated in micelles composed of poly (ethylene oxide)-poly [(R)-3-hydroxybutyrate]-poly (ethylene oxide) (PEO-PHB-PEO) triblock copolymers. Micelle size, DOX loading and DOX release were characterized. To evaluate DOX activity, micelles were tested in both monolayer cell cultures and three-dimensional (3-D) multicellular spheroids (MCS) that mimic solid tumors. Antitumor activity in vivo was further studied with tumor-bearing mice. The micelles improved the efficiency of Dox penetration in 3-D MCS compared with free DOX. Efficient cell killing by Dox-micelles in both monolayer cells and 3-D MCS was also demonstrated. Finally, DOX-loaded micelles mediate efficient tumor delivery from tail vein injections to tumor-bearing mice with much less toxicity compared with free DOX.


Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Micelas , Polietilenoglicóis/química , Polímeros/química , Esferoides Celulares/efeitos dos fármacos , Transplante Heterólogo , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacologia , Apoptose , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Teste de Materiais , Camundongos , Camundongos Nus , Estrutura Molecular , Polietilenoglicóis/metabolismo , Polímeros/metabolismo , Proibitinas
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