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1.
Semin Immunol ; 70: 101840, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37729825

RESUMO

Population aging, a pervasive global demographic trend, is anticipated to challenge health and social systems worldwide. This phenomenon is due to medical advancements enabling longer lifespans, with 20% of the US population soon to be over 65 years old. Consequently, there will be a surge in age-related diseases. Senescence, characterized by the loss of biological maintenance and homeostasis at molecular and cellular levels, either correlates with or directly causes age-related phenotypic changes. Decline of the immune system is a critical factor in the senescence process, with cancer being a primary cause of death in elderly populations. Chimeric antigen receptor (CAR) T cell therapy, an innovative approach, has demonstrated success mainly in pediatric and young adult hematological malignancies but remains largely ineffective for diseases affecting older populations, such as late-in-life B cell malignancies and most solid tumor indications. This limitation arises because CAR T cell efficacy heavily relies on the fitness of the patient-derived starting T cell material. Numerous studies suggest that T cell senescence may be a key driver of CAR T cell deficiency. This review examines correlates and underlying factors associated with favorable CAR T cell outcomes and explores potential experimental and clinically actionable strategies for T cell rejuvenation.


Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T , Adolescente , Humanos , Criança , Idoso , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T , Imunoterapia Adotiva , Envelhecimento
2.
JCI Insight ; 7(11)2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35536669

RESUMO

BACKGROUNDCOVID-19 remains a global health emergency with limited treatment options, lagging vaccine rates, and inadequate healthcare resources in the face of an ongoing calamity. The disease is characterized by immune dysregulation and cytokine storm. Cyclosporine A (CSA) is a calcineurin inhibitor that modulates cytokine production and may have direct antiviral properties against coronaviruses.METHODSTo test whether a short course of CSA was safe in patients with COVID-19, we treated 10 hospitalized, oxygen-requiring, noncritically ill patients with CSA (starting at a dose of 9 mg/kg/d). We evaluated patients for clinical response and adverse events, measured serum cytokines and chemokines associated with COVID-19 hyperinflammation, and conducted gene-expression analyses.RESULTSFive participants experienced adverse events, none of which were serious; transaminitis was most common. No participant required intensive care unit-level care, and all patients were discharged alive. CSA treatment was associated with significant reductions in serum cytokines and chemokines important in COVID-19 hyperinflammation, including CXCL10. Following CSA administration, we also observed a significant reduction in type I IFN gene expression signatures and other transcriptional profiles associated with exacerbated hyperinflammation in the peripheral blood cells of these patients.CONCLUSIONShort courses of CSA appear safe and feasible in patients with COVID-19 who require oxygen and may be a useful adjunct in resource-limited health care settings.TRIAL REGISTRATIONThis trial was registered on ClinicalTrials.gov (Investigational New Drug Application no. 149997; ClinicalTrials.gov NCT04412785).FUNDINGThis study was internally funded by the Center for Cellular Immunotherapies.


Assuntos
Tratamento Farmacológico da COVID-19 , Ciclosporina/uso terapêutico , Citocinas , Humanos , Oxigênio , SARS-CoV-2
3.
Nat Commun ; 11(1): 2176, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358491

RESUMO

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD40/agonistas , Carcinoma Ductal Pancreático/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Antígenos CD40/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética
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