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1.
Nat Microbiol ; 5(10): 1185-1191, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32908214

RESUMO

Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.


Assuntos
Anticorpos Facilitadores , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Vacinas Virais/efeitos adversos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Anticorpos Facilitadores/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Humanos , Imunização Passiva/efeitos adversos , Técnicas In Vitro , Modelos Imunológicos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Doenças Respiratórias/etiologia , Doenças Respiratórias/imunologia , Fatores de Risco , Segurança , Vacinas Virais/imunologia
2.
Ann Hematol ; 99(11): 2589-2598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892275

RESUMO

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Compostos de Boro/administração & dosagem , Glicina/análogos & derivados , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Indução de Remissão , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
3.
Lancet Oncol ; 21(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888453

RESUMO

BACKGROUND: There is a strong unmet need to improve systemic therapy in mesothelioma. Chemotherapy with cisplatin and pemetrexed improves survival in malignant pleural mesothelioma, and immune checkpoint inhibitors are an emerging treatment in this disease. We aimed to evaluate the activity of durvalumab, an anti-PD-L1 antibody, given during and after first-line chemotherapy with cisplatin and pemetrexed in patients with advanced malignant pleural mesothelioma. METHODS: DREAM was a multicentre, single-arm, open-label, phase 2 trial done in nine hospitals in Australia. Eligible patients were aged 18 years or older and had histologically confirmed malignant pleural mesothelioma considered unsuitable for cancer-directed surgery, an Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease as per the modified Response Evaluation Criteria in Solid Tumors version 1.0 (mRECIST) for mesothelioma that was previously untreated with systemic therapy. All histological subtypes were eligible. The first six participants were treated for two cycles in a safety run-in. All participants received cisplatin 75 mg/m2, pemetrexed 500 mg/m2, and durvalumab 1125 mg intravenously on day 1 of a 3-weekly schedule for a maximum of six cycles. Change from cisplatin to carboplatin with an area under the curve of 5 was permitted. Durvalumab was continued for a maximum of 12 months. The primary endpoint was progression-free survival at 6 months, measured according to mRECIST for malignant pleural mesothelioma and analysed in the intention-to-treat population. Safety analyses included all participants who receive at least one dose of any study drug. This study is registered with the Australia New Zealand Clinical Trials Registry, ACTRN12616001170415. FINDINGS: Between Dec 28, 2016, and Sept 27, 2017, 55 participants were enrolled. 54 patients were eligible and were followed up for a median of 28·2 months (IQR 26·5-30·2). 31 (57%; 95% CI 44-70) of 54 patients were alive and progression-free at 6 months. The most common grade 3-4 adverse events were neutropenia (seven [13%] patients), nausea (six [11%]), and anaemia (four [7%]). A total of 60 serious adverse events occurred in 29 participants, five of which were considered possibly related to durvalumab. Five patients died during the study treatment; none of these five deaths were attributed to study treatment. INTERPRETATION: The combination of durvalumab, cisplatin, and pemetrexed has promising activity and an acceptable safety profile that warrants further investigation in a randomised phase 3 trial. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/administração & dosagem , Neoplasias Pleurais/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália/epidemiologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Cisplatino/efeitos adversos , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma/genética , Mesotelioma/imunologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão
4.
Drug Des Devel Ther ; 14: 2607-2611, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753842

RESUMO

In March 2020, the WHO declared the COVID-19 disease as a pandemic disease. There have been studies on the COVID-19 to find a certain treatment, but yet, there is no certain cure. In this article, we present a possible way to treat severe cases of COVID-19. Based on the previous studies, there are similarities between the spike antigens of SARS-CoV and SARS-CoV-2 viruses. It is expected that these similarities (structural and affinity to the receptor of ACE2) can lead to the same pathophysiological activity of the virus by the use of ACE2 and FcγRII (the antibody-dependent enhancement mechanism). Therefore, we propose a way of washing out (by plasmapheresis) the possible antibodies against the spike protein of the virus out of patients' plasma to stop the antibody-dependent enhancement (ADE)-mediated infection of the immune system cells at the first phase of the treatment and simultaneous use of the anti-ACE2 with anti-FcγRII monoclonal antibodies at the second phase. We propose these procedures for the patients that have no significant response for typical anti-viral, ARDS and conservative therapies, and the disease persists or progresses despite sufficient therapies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Infecções por Coronavirus/terapia , Plasmaferese/métodos , Pneumonia Viral/terapia , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Pandemias , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de IgG/imunologia , Índice de Gravidade de Doença
5.
Nat Rev Immunol ; 20(10): 633-643, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32782358

RESUMO

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Facilitadores/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Receptores de IgG/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Dengue/tratamento farmacológico , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/genética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais , Internalização do Vírus/efeitos dos fármacos
6.
Lancet Oncol ; 21(9): 1155-1164, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32771088

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto Jovem
7.
Medicine (Baltimore) ; 99(32): e21480, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769882

RESUMO

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs into clinical practice has dramatically improved the clinical outcomes of individuals with rheumatoid arthritis (RA). We are conducting the IFX-SIRIUS STUDY I that evaluates whether switching from originator infliximab (IFX) to its biosimilar, CT-P13, is not inferior in maintaining nonclinical relapse to continue treatment with originator IFX in patients with RA achieving clinical remission. It is the next great issue whether disease activity can be maintained in good condition after discontinuation of CT-P13 because no evidence is available regarding the clinical value of discontinuing biosimilars in patients with RA. Thus, we will evaluate whether a condition without clinical relapse will be maintained after discontinuation of CT-P13 in patients with RA, achieving clinical remission or low disease activity during the IFX-SIRIUS STUDY I. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm clinical trial with a 48-week follow-up. Patients with RA who are treated with CT-P13 and sustained nonclinical relapse during the IFX-SIRIUS STUDY I will be included. Patients will discontinue CT-P13 after the study period of the IFX-SIRIUS STUDY I. We will evaluate disease activity by clinical disease activity indices and musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who do not have clinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of multiple biomarkers, such as cytokines and chemokines. In addition, if a clinical relapse occurs in patients after the discontinuation of CT-P13, we will evaluate the effectiveness and safety of restarting CT-P13. DISCUSSION: The study results are expected to show the clinical benefit of the discontinuation of CT-P13 and effectiveness and safety of restarting CT-P13 after clinical relapse. The strength of this study is to prospectively evaluate the therapeutic effectiveness by not only clinical disease activity indices but also standardized MSUS findings in multiple centers. We will explore whether parameters at baseline can predict a nonclinical relapse after the discontinuation of CT-P13 by integrating multilateral assessments, that is, patient's characteristics, clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on April 20, 2020 as jRCTs071200007.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/patologia , Medicamentos Biossimilares/administração & dosagem , Substituição de Medicamentos , Infliximab/administração & dosagem , Adulto , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/análise , Estudos de Equivalência como Asunto , Feminino , Humanos , Quimioterapia de Indução , Japão , Masculino , Recidiva , Resultado do Tratamento , Ultrassonografia
8.
Nat Commun ; 11(1): 3736, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719371

RESUMO

A replication-competent vesicular stomatitis virus vaccine expressing the Ebola virus (EBOV) glycoprotein (GP) (rVSV-ZEBOV) was successfully used during the 2013-16 EBOV epidemic. Additionally, chimeric and human monoclonal antibodies (mAb) against the EBOV GP have shown promise in animals and humans when administered therapeutically. Uncertainty exists regarding the efficacy of postexposure antibody treatments in the event of a known exposure of a recent rVSV-ZEBOV vaccinee. Here, we model a worst-case scenario using rhesus monkeys vaccinated or unvaccinated with the rVSV-ZEBOV vaccine. We demonstrate that animals challenged with a uniformly lethal dose of EBOV one day following vaccination, and then treated with the anti-EBOV GP mAb MIL77 starting 3 days postexposure show no evidence of clinical illness and survive challenge. In contrast, animals receiving only vaccination or only mAb-based therapy become ill, with decreased survival compared to animals vaccinated and subsequently treated with MIL77. These results suggest that rVSV-ZEBOV augments immunotherapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Vacinas contra Ebola/imunologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Profilaxia Pós-Exposição , Vacinação , Vírus da Estomatite Vesicular Indiana/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Estimativa de Kaplan-Meier , Macaca mulatta , Resultado do Tratamento , Carga Viral/imunologia
9.
Cancer Treat Rev ; 89: 102065, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32653806

RESUMO

To date, much progress has been made in early-stage extranodal NK/T-cell lymphoma (ENKTCL), and risk-adapted therapy with radiotherapy (RT) alone for the low-risk group and RT combined with asparaginase-based chemotherapy (CT) for the high-risk group yields favorable outcomes. However, optimal treatment strategies have not been defined yet for advanced-stage ENKTCL. Historically, ENKTCL responded poorly to conventional anthracycline-based chemotherapy probably because of inherent multidrug resistance (MDR). The fact that ENKTCL cells lack asparagine synthetase (ASNS) activity warranted the use of L-asparaginase or pegaspargase as frontline chemotherapies. Even though, due to high mortality of the disease, approximately 50% patients failing the frontline therapy arrived at dismal clinical outcomes with a median progression-free survival (PFS) less than 8 months. As distinctive molecular and biological subgroups are increasingly discovered within the disease entity of ENKTCL, novel targeted therapies and immunotherapy are of the urgent need for those heterogeneous subgroups. In this review, we sought to summarize the preclinical and clinical results of 6 categories of promising targeted therapy and immunotherapy for the treatment of ENKTCL, including monoclonal antibodies, immune checkpoint inhibitors, small-molecular inhibitors, epigenetic therapy, immunomodulatory drugs, and adoptive T-cell therapy, and these might change the landscape of treatment for ENKTCL in the near future.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/terapia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Imunoterapia/métodos , Imunoterapia Adotiva , Terapia de Alvo Molecular/métodos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/farmacologia
10.
N Engl J Med ; 383(5): 415-425, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32726528

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose. METHODS: In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose. RESULTS: From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions. CONCLUSIONS: A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antivirais/administração & dosagem , Recém-Nascido Prematuro , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano , Infecções Respiratórias/prevenção & controle , Proteínas Virais de Fusão/antagonistas & inibidores , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antivirais/efeitos adversos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Lactente , Recém-Nascido , Injeções Intramusculares , Estimativa de Kaplan-Meier , Masculino , Distribuição de Poisson , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia
11.
J Am Acad Dermatol ; 83(5): 1523-1526, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32622891
12.
Medicine (Baltimore) ; 99(28): e21273, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664183

RESUMO

BACKGROUND: The combination of durvalumab and tremelimumab results in clinical benefit, with a tolerable safety profile in patients with solid tumors. OBJECTIVE: To evaluate the efficacy and safety of durvalumab in combination with tremelimumab compared with either drug alone. METHODS: The online databases (PubMed, Web of Science, EMBASE, and Cochrane Library) were searched for potential clinical studies up to Nov 26, 2019. Eligible studies were prospective and registered clinical trials. Pooled odds ratios for objective response rate and disease control rate and pooled risk ratios for treatment-related adverse events were meta-analyzed. A random-effect model was used due to the synthesis of different cancer types. RESULTS: Overall, 5 studies were eligible for systematic review, 3 of which were further meta-analyzed. Durvalumab plus tremelimumab was superior to tremelimumab monotherapy in improving disease control rate in head and neck squamous cell carcinoma. However, there were no significant differences between dual immunotherapy and mono-immunotherapy in pancreatic ductal adenocarcinoma and gastric and gastroesophageal junction adenocarcinoma. Additionally, pooled analyses illustrated that no significant differences in treatment-related adverse events were displayed between the 2 groups. CONCLUSION: Durvalumab and tremelimumab combination therapy had a good safety profile and resulted in clinical benefit in head and neck squamous cell carcinoma. Future explorations are needed to further confirm the application of durvalumab plus tremelimumab.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
13.
Bull Cancer ; 107(5S): eS8-eS15, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620213

RESUMO

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. METHODS/DESIGN: NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. DISCUSSION: NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Terapia Neoadjuvante , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/uso terapêutico
14.
Lancet ; 396(10245): 186-197, 2020 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-32682484

RESUMO

BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile. FUNDING: Amgen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Doença Crônica , Dexametasona/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Resultado do Tratamento , Adulto Jovem
15.
Lancet Oncol ; 21(8): 1066-1076, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32653053

RESUMO

BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). FUNDING: MacroGenics.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Pharmaceut Med ; 34(4): 223-231, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32535732

RESUMO

At present, there are no proven agents for treatment of coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. The novel coronavirus SARS-CoV-2 that causes COVID-19 invokes a hyperinflammatory state driven by multiple cells and mediators like interleukin (IL)-1, IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNFα), etc. Considering the proven role of cytokine dysregulation in causing this hyperinflammation in the lungs with IL-6 being a key driver, particularly in seriously ill COVID-19 patients, it is crucial to further explore selective cytokine blockade with drugs like the IL-6 inhibitors tocilizumab, sarilumab, and siltuximab. These targeted monoclonal antibodies can dampen the downstream IL-6 signaling pathways, which can lead to decreased cell proliferation, differentiation, oxidative stress, exudation, and improve clinical outcomes in patients with evident features of cytokine-driven inflammation like persistent fever, dyspnea and elevated markers. Preliminary evidence has come for tocilizumab from some small studies, and interim analysis of a randomized controlled trial; the latter also being available for sarilumab. International guidelines do include IL-6 inhibitors as one of the options available for severe or critically ill patients. There has been increased interest in evaluating these drugs with a series of clinical trials being registered and conducted in different countries. The level of investigation though perhaps needs to be further intensified as there is a need to focus on therapeutic options that can prove to be 'life-saving' as the number of COVID-19 fatalities worldwide keeps increasing alarmingly. IL-6 inhibitors could be one such treatment option, with generation of more evidence and completion of a larger number of systematic studies.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Citocinas/imunologia , Humanos , Interleucina-6/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia
17.
Life Sci ; 256: 117985, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32562692

RESUMO

AIMS: To assess the combination therapy of anti-CD20 mabs and adenovirus-mediated interleukin-10 (IL-10) gene delivery on the prevention of type 1 diabetes (T1D) in non-obese diabetes (NOD) mice. MAIN METHODS: In present study, we simultaneously blocked the B cell interactions and recovered the Th cell subset proportion by using through anti-CD20 Mab and adenovirus-mediated gene delivery of IL-10, respectively. After 9 consecutive days of combination therapy, various measurements, including hematoxylin-eosin staining (HE), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling assay (TUNEL), immunohistochemistry, ELISA, PCR and western blot were applied to further assess the efficacy. KEY FINDINGS: The results suggested that the combination intervention reduced the T1D-associated morbidity of NOD mice, promote insulin secretion, control blood glucose and ease pancreatitis. Moreover, the combination therapy might play a protective role in pancreatic ß cells by suppressing the expression of TNF-α and Fas, blocking the Caspase-8 and Caspase-3 apoptotic pathways and activating the Bcl-2 anti-apoptotic pathway. Finally, the combination intervention may up-regulate the gene expression of CK-19 and PDX-1 and further accelerate the differentiation and proliferation of pancreatic ß cells. SIGNIFICANCE: Therefore, the combination intervention with anti-CD20 mabs and the IL-10 gene plays a role in the prevention of T1D to some extent in NOD mice.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antígenos CD20/administração & dosagem , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Interleucina-10/administração & dosagem , Pancreatite/tratamento farmacológico , Adenoviridae/genética , Animais , Anticorpos Monoclonais/genética , Antígenos CD20/genética , Apoptose/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Quimioterapia Combinada , Feminino , Interleucina-10/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pancreatite/genética , Pancreatite/patologia
20.
Cell ; 182(1): 73-84.e16, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32425270

RESUMO

The COVID-19 pandemic urgently needs therapeutic and prophylactic interventions. Here, we report the rapid identification of SARS-CoV-2-neutralizing antibodies by high-throughput single-cell RNA and VDJ sequencing of antigen-enriched B cells from 60 convalescent patients. From 8,558 antigen-binding IgG1+ clonotypes, 14 potent neutralizing antibodies were identified, with the most potent one, BD-368-2, exhibiting an IC50 of 1.2 and 15 ng/mL against pseudotyped and authentic SARS-CoV-2, respectively. BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice. Additionally, the 3.8 Å cryo-EM structure of a neutralizing antibody in complex with the spike-ectodomain trimer revealed the antibody's epitope overlaps with the ACE2 binding site. Moreover, we demonstrated that SARS-CoV-2-neutralizing antibodies could be directly selected based on similarities of their predicted CDR3H structures to those of SARS-CoV-neutralizing antibodies. Altogether, we showed that human neutralizing antibodies could be efficiently discovered by high-throughput single B cell sequencing in response to pandemic infectious diseases.


Assuntos
Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/isolamento & purificação , Linfócitos B/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Análise de Célula Única , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/metabolismo , Convalescença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Camundongos , Pandemias , Análise de Sequência de RNA , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Éxons VDJ
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