Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Clin Trials ; 21(4): 491-499, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38366865

RESUMEN

BACKGROUND/AIMS: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, 103.4 million cases and 1.1 million deaths have occurred nationally as of November 2023. Despite the benefit of mitigating measures, the pandemic's effect on participant safety is rarely documented. METHODS: This study assessed noncompliance occurring from July 2019 to August 2021 that were stratified by the date of noncompliance (before or after restrictions). Events were described by size, site, noncompliance type, primary category, subcategory, and cause. In addition, noncompliance associated with COVID-19 was analyzed to determine characteristics. RESULTS: In total, 323 noncompliance events occurred across 21,146 participants at risk in 35 protocols. The overall rate of noncompliance increased from 0.008 events per participant to 0.022 events per participant after the COVID-19 restrictions (p < 0.001). For onsite protocols, the median within protocol change in rates was 0.001 (interquartile range = 0.141) after the onset of COVID-19 restrictions (p = 0.54). For large-sized protocols (n ≥ 100), the median within protocol change in rates was also 0.001 (interquartile range = 0.017) after COVID-19 restrictions (p = 0.15). For events related to COVID-19 restrictions, 160/162 (99%) were minor deviations, 161/162 (99%) were procedural noncompliance, and 124/162 (77%) were an incomplete study visit. CONCLUSION: These noncompliance events have implications for clinical trial methodology because nonadherence to trial design can lead to participant safety concerns and loss of trial data validity. Protocols should be written to better facilitate the capture of all safety and efficacy data. This recommendation should be considered when changes occur to the protocol environment that are outside of the study team's control.


Asunto(s)
COVID-19 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , SARS-CoV-2 , Protocolos Clínicos , Pandemias , Proyectos de Investigación , Cooperación del Paciente/estadística & datos numéricos
2.
Artículo en Inglés | MEDLINE | ID: mdl-37147136

RESUMEN

BACKGROUND AND OBJECTIVES: SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC). METHODS: Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection. Autonomic function and CSF immunophenotypic analysis were compared with healthy volunteers (HVs) without prior SARS-CoV-2 infection tested using the same methodology. RESULTS: Participants were mostly female (83%), with a mean age of 45 ± 11 years. The median time of evaluation was 9 months after COVID-19 (range 3-12 months), and most (11/12, 92%) had a history of only a mild infection. The most common neuro-PASC symptoms were cognitive difficulties and fatigue, and there was evidence for mild cognitive impairment in half of the patients (MoCA score <26). The majority (83%) had a very disabling disease, with Karnofsky Performance Status ≤80. Smell testing demonstrated different degrees of microsmia in 8 participants (66%). Brain MRI scans were normal, except 1 patient with bilateral olfactory bulb hypoplasia that was likely congenital. CSF analysis showed evidence of unique intrathecal oligoclonal bands in 3 cases (25%). Immunophenotyping of CSF compared with HVs showed that patients with neuro-PASC had lower frequencies of effector memory phenotype both for CD4+ T cells (p < 0.0001) and for CD8+ T cells (p = 0.002), an increased frequency of antibody-secreting B cells (p = 0.009), and increased frequency of cells expressing immune checkpoint molecules. On autonomic testing, there was evidence for decreased baroreflex-cardiovagal gain (p = 0.009) and an increased peripheral resistance during tilt-table testing (p < 0.0001) compared with HVs, without excessive plasma catecholamine responses. DISCUSSION: CSF immune dysregulation and neurocirculatory abnormalities after SARS-CoV-2 infection in the setting of disabling neuro-PASC call for further evaluation to confirm these changes and explore immunomodulatory treatments in the context of clinical trials.


Asunto(s)
Linfocitos T CD8-positivos , COVID-19 , Femenino , Masculino , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Encéfalo , Catecolaminas
3.
Ann Neurol ; 93(3): 427-430, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36546649

RESUMEN

The subspecialty of experimental neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated. The burgeoning opportunities in the field mandate that training address the challenges of overcoming obstacles in therapeutic discovery, implementation science, and development of affordable and equitably available treatments. ANN NEUROL 2023;93:427-430.


Asunto(s)
Industria Farmacéutica , Olas de Marea , Humanos
4.
Continuum (Minneap Minn) ; 28(6): 1817-1834, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36537982

RESUMEN

PURPOSE OF REVIEW: The discipline of experimental neurotherapeutics targets the process and operation of translating scientific discoveries into new treatments for neurologic diseases and has been instrumental in the progression of many areas of neurology. RECENT FINDINGS: From the US Food and Drug Administration (FDA) market approval of the first systemic in vivo gene therapy in neurology to multiple current gene-targeting therapeutics, monoclonal antibodies, and new drugs under development or approved in the last several years, the field of experimental neurotherapeutics has a presence in every neuromuscular clinic in the United States. SUMMARY: This article provides an overview of experimental neurotherapeutics with guidance on the clinical trials landscape, using examples in the field of neuromuscular disease. It covers the regulatory framework, clinical trial methodology, and offers advice on common pitfalls encountered when embarking on a clinical trials program in the clinic.


Asunto(s)
Anticuerpos Monoclonales , Enfermedades Neuromusculares , Humanos , Estados Unidos , United States Food and Drug Administration , Terapia Genética , Enfermedades Neuromusculares/terapia , Aprobación de Drogas
5.
Neurotherapeutics ; 19(5): 1503-1506, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36083396

RESUMEN

Drug development abounds with corporate pharmaceutical capital investment and expenditure costs for new therapeutics. However, there is little data on the human investment, in particular, the number of participants required or the potential burden on and cost to individual trial participants so instrumental to this endeavor. Indeed, the human participant burden in clinical trials is poorly, if at all, described in the literature and we could identify no reports that have detailed the participant burden unique to neurology trials. The cost of clinical trials to participants, including the unique circumstances affecting enrollment of diverse participant populations, has only begun to be reflected in the wider clinical trial literature. Additionally, details of the indirect costs, including time commitment, out-of-pocket expenses, emotional expenditure, and potential loss of enrollment into a more successful trial by participants in trials that fail - the majority in the field - is also particularly striking in the lack of representation in the literature. Even in successful clinical trials, participants in the placebo group face both an emotional burden and medical risk of morbidity and mortality without potential offsetting therapeutic benefit.


Asunto(s)
Neurología , Humanos , Preparaciones Farmacéuticas
6.
Ann Neurol ; 92(4): 545-561, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35801347

RESUMEN

OBJECTIVE: Human endogenous retroviruses have been implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Expression of human endogenous retrovirus K (HERV-K) subtype HML-2 envelope (Env) in human neuronal cultures and in transgenic mice results in neurotoxicity and neurodegeneration, and mice expressing HML-2 Env display behavioral and neuromuscular characteristics resembling ALS. This study aims to characterize the neurotoxic properties of HML-2 Env. METHODS: Env neurotoxicity was detected in ALS cerebrospinal fluid and confirmed using recombinant Env protein in a cell-based assay and a mouse model. The mechanism of neurotoxicity was assessed with immunoprecipitation followed by mass spectrometry and Western blot, and by screening a panel of inhibitors. RESULTS: We observed that recombinant HML-2 Env protein caused neurotoxicity resulting in neuronal cell death, retraction of neurites, and decreased neuronal electrical activity. Injection of the Env protein into the brains of mice also resulted in neuronal cell death. HML-2 Env protein was also found in the cerebrospinal fluid of patients with sporadic ALS. The neurotoxic properties of the Env and the cerebrospinal fluid could be rescued with the anti-Env antibody. The Env was found to bind to CD98HC complexed to ß1 integrin on the neuronal cell surface. Using a panel of compounds to screen for their ability to block Env-induced neurotoxicity, we found that several compounds were protective and are linked to the ß1 integrin pathway. INTERPRETATION: HERV-K Env is released extracellularly in ALS and causes neurotoxicity via a novel mechanism. Present results pave the way for new treatment strategies in sporadic ALS. ANN NEUROL 2022;92:545-561.


Asunto(s)
Esclerosis Amiotrófica Lateral , Retrovirus Endógenos , Esclerosis Amiotrófica Lateral/genética , Animales , Productos del Gen env , Humanos , Integrina beta1 , Ratones , Ratones Transgénicos
7.
Lancet Neurol ; 20(8): 639-652, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34302788

RESUMEN

BACKGROUND: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe. METHODS: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 106 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 106 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783. FINDINGS: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months. INTERPRETATION: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients. FUNDING: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.


Asunto(s)
Virus BK/inmunología , Inmunoterapia/métodos , Leucoencefalopatía Multifocal Progresiva/terapia , Linfocitos T/inmunología , Adulto , Anciano , Donantes de Sangre , Estudios de Cohortes , Determinación de Punto Final , Estudios de Factibilidad , Femenino , Humanos , Inmunoterapia/efectos adversos , Virus JC/inmunología , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Proyectos Piloto , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
8.
Neurotherapeutics ; 18(2): 859-865, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33475954

RESUMEN

In an effort to minimize protocol noncompliance in neurological research studies that can potentially compromise patient safety, delay completion of the study, and result in premature termination and added costs, we determined the effect of investigator trainings and site initiation visits (SIVs) on the occurrence of noncompliance events. Results of protocol audits conducted at the National Institute of Neurological Disorders and Stroke from 2003 to 2019 on 97 research protocols were retrospectively analyzed. Based on the depth of auditing and provision of investigator research training, audit data were separated into four arms: 1) Early Period, 2003 to 2012; 2) Middle Period, 2013 to 2016; and Late Period, 2017 to 2019, further divided into 3) Late Period without SIVs; and 4) Late Period with SIVs. Events of noncompliance were classified by the type of protocol deviation, the category, and the cause. In total, 952 events occurred across 1080 participants. Protocols audited during the Middle Period, compared to the Early Period, showed a decrease in the percentage of protocols with at least 1 noncompliance event. Protocols with SIVs had a further decrease in major, minor, procedural, eligibility, and policy events. Additionally, protocols audited during the Early Period had on average 0.46 major deviations per participant, compared to 0.26 events in protocols audited during the Middle Period, and 0.08 events in protocols audited during the Late Period with SIVs. Protocol deviations and noncompliance events in neurological clinical trials can be reduced by targeted investigator trainings and SIVs. These measures have major impacts on the integrity, safety, and effectiveness of human subjects research in neurology.


Asunto(s)
Competencia Clínica/normas , Protocolos Clínicos/normas , Experimentación Humana/normas , National Institute of Neurological Disorders and Stroke (U.S.)/normas , Enfermedades del Sistema Nervioso/terapia , Neurología/normas , Investigación Biomédica/métodos , Investigación Biomédica/normas , Bases de Datos Factuales/normas , Humanos , Enfermedades del Sistema Nervioso/epidemiología , Neurología/educación , Neurología/métodos , Sujetos de Investigación , Estados Unidos
9.
Lancet Infect Dis ; 20(10): e251-e260, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32768390

RESUMEN

The term metagenomics refers to the use of sequencing methods to simultaneously identify genomic material from all organisms present in a sample, with the advantage of greater taxonomic resolution than culture or other methods. Applications include pathogen detection and discovery, species characterisation, antimicrobial resistance detection, virulence profiling, and study of the microbiome and microecological factors affecting health. However, metagenomics involves complex and multistep processes and there are important technical and methodological challenges that require careful consideration to support valid inference. We co-ordinated a multidisciplinary, international expert group to establish reporting guidelines that address specimen processing, nucleic acid extraction, sequencing platforms, bioinformatics considerations, quality assurance, limits of detection, power and sample size, confirmatory testing, causality criteria, cost, and ethical issues. The guidance recognises that metagenomics research requires pragmatism and caution in interpretation, and that this field is rapidly evolving.


Asunto(s)
Metagenómica/métodos , Metagenómica/estadística & datos numéricos , Biología Computacional , Humanos , Epidemiología Molecular , Proyectos de Investigación/normas
10.
Neurology ; 94(15): 673-677, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32165447

RESUMEN

Medical students choose neurology for many reasons, including interest in neuroscience, the intellectual challenge of diagnosing and treating disorders of the nervous system, and the opportunity for continuity of care. Neurologists have great flexibility in choice of practice environment, ranging from an exclusively inpatient setting to a strictly clinic-based practice. The purpose of this article is to provide practical, actionable, systematic advice for medical students at every level of training on how to prepare for a neurology residency application and a career in neurology. To this end, we include a timeline designed to guide students' efforts throughout their medical school education. These recommendations incorporate the viewpoints of key participants in many aspects of medical student and resident neuroscience education. The timeline and recommendations outline a suggested early, proactive approach, but should not discourage students from considering neurology at a later point in their training. Neurology remains an inclusive specialty that welcomes students of all backgrounds and offers a rewarding career in one of the most exciting fields in medicine.


Asunto(s)
Selección de Profesión , Educación Médica , Neurología/educación , Estudiantes de Medicina , Femenino , Humanos , Internado y Residencia , Masculino , Medicina , Facultades de Medicina , Encuestas y Cuestionarios
11.
Clin Case Rep ; 8(1): 24-32, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31998480

RESUMEN

We report a case of nivolumab-induced delayed-onset aseptic meningitis and a case of limbic encephalitis and peripheral nerve palsy with toxicity relapse 6 months after initial presentation. The atypical presentations contribute to our knowledge of these rare events and reinforce the necessity for vigilant monitoring and a multidisciplinary treatment approach.

12.
J Virol ; 94(3)2020 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-31694954

RESUMEN

A disease of more than 39.6 million people worldwide, HIV-1 infection has no curative therapy. To date, one man has achieved a sterile cure, with millions more hoping to avoid the potential pitfalls of lifelong antiretroviral therapy and other HIV-related disorders, including neurocognitive decline. Recent developments in immunotherapies and gene therapies provide renewed hope in advancing efforts toward a sterilizing or functional cure. On the horizon is research concentrated in multiple separate but potentially complementary domains: vaccine research, viral transcript editing, T-cell effector response targeting including checkpoint inhibitors, and gene editing. Here, we review the concept of targeting the HIV-1 tissue reservoirs, with an emphasis on the central nervous system, and describe relevant new work in functional cure research and strategies for HIV-1 eradication.


Asunto(s)
Reservorios de Enfermedades , Infecciones por VIH/terapia , VIH-1/fisiología , Encéfalo , Sistemas CRISPR-Cas , Edición Génica/métodos , Terapia Genética/métodos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/inmunología , Humanos , Latencia del Virus
13.
AIDS ; 33 Suppl 2: S145-S157, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31789815

RESUMEN

OBJECTIVE: The aim of this study was to measure the protein concentration and biological activity of HIV-1 Tat in cerebrospinal fluid (CSF) of individuals on suppressive antiretroviral therapy (ART). DESIGN: CSF was collected from 68 HIV-positive individuals on ART with plasma viral load less than 40 copies/ml, and from 25 HIV-negative healthy controls. Duration of HIV infection ranged from 4 to more than 30 years. METHODS: Tat levels in CSF were evaluated by an ELISA. Tat protein and viral RNA were quantified from exosomes isolated from CSF, followed by western blot or quantitative reverse transcription PCR, respectively. Functional activity of Tat was assessed using an LTR transactivation assay. RESULTS: Tat protein was detected in 36.8% of CSF samples from HIV-positive patients. CSF Tat concentration increased in four out of five individuals after initiation of therapy, indicating that Tat was not inhibited by ART. Similarly, exosomes from 34.4% of CSF samples were strongly positive for Tat protein and/or TAR RNA. Exosomal Tat retained transactivation activity in a CEM-LTR reporter assay in 66.7% of samples assayed, which indicates that over half of the Tat present in CSF is functional. Presence of Tat in CSF was highly associated with previous abuse of psychostimulants (cocaine or amphetamines; P = 0.01) and worse performance in the psychomotor speed (P = 0.04) and information processing (P = 0.02) cognitive domains. CONCLUSION: Tat and TAR are produced in the central nervous system despite adequate ART and are packaged into CSF exosomes. Tat remains biologically active within this compartment. These studies suggest that Tat may be a quantifiable marker of the viral reservoir and highlight a need for new therapies that directly inhibit Tat.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , ARN Viral/líquido cefalorraquídeo , Elementos de Respuesta , Transcripción Genética , Activación Transcripcional , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/líquido cefalorraquídeo , Femenino , Infecciones por VIH/virología , Duplicado del Terminal Largo de VIH , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Carga Viral
14.
Ann Neurol ; 86(6): 878-884, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31600832

RESUMEN

OBJECTIVE: JC virus (JCV) infection is a lytic infection of oligodendrocytes in progressive multifocal leukoencephalopathy; less common forms of central nervous system manifestations associated with JCV infection include granule cell neuronopathy, encephalopathy, and meningitis. Presented is the first case of fatal JCV encephalopathy after immunosuppressive therapy that included ruxolitinib. METHODS: Postmortem analysis included next generation sequencing, Sanger sequencing, tissue immunohistochemistry, and formalin-fixed hemisphere 7T magnetic resonance imaging. RESULTS: JCV DNA isolated from postmortem tissue samples identified a novel 12bp insertion that altered the transcription site binding pattern in an otherwise "wild-type virus," which has long been thought to be the nonpathogenic form of JCV. Anti-VP1 staining demonstrated infection in cortical neurons, hippocampal neurons, and glial and endothelial cells. INTERPRETATION: This expands the spectrum of identified JCV diseases associated with broad-spectrum immunosuppression, including JAK-STAT inhibitors, and sheds light on an additional neurotropic virus strain of the archetype variety. ANN NEUROL 2019;86:878-884.


Asunto(s)
Encefalopatías/tratamiento farmacológico , Encefalopatías/genética , Virus JC/genética , Quinasas Janus/genética , Pirazoles/uso terapéutico , Adolescente , Secuencia de Bases , Encefalopatías/diagnóstico por imagen , Resultado Fatal , Femenino , Humanos , Virus JC/aislamiento & purificación , Nitrilos , Pirimidinas
15.
Ann Neurol ; 86(5): 695-703, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31461177

RESUMEN

OBJECTIVE: To determine the underlying etiology in a patient with progressive dementia with extrapyramidal signs and chronic inflammation referred to the National Institutes of Health Undiagnosed Diseases Program. METHODS: Extensive investigations included metabolic profile, autoantibody panel, infectious etiologies, genetic screening, whole exome sequencing, and the phage-display assay, VirScan, for viral immune responses. An etiological diagnosis was established postmortem. RESULTS: Using VirScan, enrichment of dengue viral antibodies was detected in cerebrospinal fluid as compared to serum. No virus was detected in serum or cerebrospinal fluid, but postmortem analysis confirmed dengue virus in the brain by immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, and sequencing. Dengue virus was also detectable by polymerase chain reaction and sequencing from brain biopsy tissue collected 33 months antemortem, confirming a chronic infection despite a robust immune response directed against the virus. Immunoprofiling and whole exome sequencing of the patient did not reveal any immunodeficiency, and sequencing of the virus demonstrated wild-type dengue virus in the central nervous system. INTERPRETATION: Dengue virus is the most common arbovirus worldwide and represents a significant public health concern. Infections with dengue virus are usually self-limiting, and chronic dengue infections have not been previously reported. Our findings suggest that dengue virus infections may persist in the central nervous system causing a panencephalitis and should be considered in patients with progressive dementia with extrapyramidal features in endemic regions or with relevant travel history. Furthermore, this work highlights the utility of comprehensive antibody profiling assays to aid in the diagnosis of encephalitis of unknown etiology. ANN NEUROL 2019;86:695-703.


Asunto(s)
Dengue/complicaciones , Dengue/patología , Encefalitis Viral/etiología , Encefalitis Viral/patología , Enfermedad Crónica , Demencia , Virus del Dengue , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad
16.
N Engl J Med ; 380(17): 1597-1605, 2019 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-30969503

RESUMEN

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection that is caused by the JC virus and is typically fatal unless immune function can be restored. Programmed cell death protein 1 (PD-1) is a negative regulator of the immune response that may contribute to impaired viral clearance. Whether PD-1 blockade with pembrolizumab could reinvigorate anti-JC virus immune activity in patients with PML was unknown. METHODS: We administered pembrolizumab at a dose of 2 mg per kilogram of body weight every 4 to 6 weeks to eight adults with PML, each with a different underlying predisposing condition. Each patient received at least one dose but no more than three doses. RESULTS: Pembrolizumab induced down-regulation of PD-1 expression on lymphocytes in peripheral blood and in cerebrospinal fluid (CSF) in all eight patients. Five patients had clinical improvement or stabilization of PML accompanied by a reduction in the JC viral load in the CSF and an increase in in vitro CD4+ and CD8+ anti-JC virus activity. In the other three patients, no meaningful change was observed in the viral load or in the magnitude of antiviral cellular immune response, and there was no clinical improvement. CONCLUSIONS: Our findings are consistent with the hypothesis that in some patients with PML, pembrolizumab reduces JC viral load and increases CD4+ and CD8+ activity against the JC virus; clinical improvement or stabilization occurred in five of the eight patients who received pembrolizumab. Further study of immune checkpoint inhibitors in the treatment of PML is warranted. (Funded by the National Institutes of Health.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Factores Inmunológicos/uso terapéutico , Virus JC/aislamiento & purificación , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Líquido Cefalorraquídeo/virología , Regulación hacia Abajo , Femenino , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Leucoencefalopatía Multifocal Progresiva/inmunología , Recuento de Linfocitos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Carga Viral , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...