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2.
Front Immunol ; 11: 1844, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903555

RESUMO

With the onset of the global pandemic in 2020 of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), there has been increasing research activity around certain disease-modifying drugs that are used for the management of inflammatory disorders such as rheumatoid arthritis, spondyloarthrosis, psoriatic arthritis, systemic lupus erythematosus, and inflammatory bowel disease for managing coronavirus symptoms. In the conditions mentioned, many people are on long-term treatment with agents including hydroxychloroquine, tumor necrosis factor alpha (TNFα) inhibitor drugs, other biologic agents such as monoclonal antibodies to IL-6 and Janus kinase inhibitors including baricitinib and tofacitinib, which are used to control inflammatory responses in their respective auto-immune condition. There is emerging data that immunomodulatory drugs could be protective at reducing certain features of SARS-CoV-2 and improving recovery. In addition, it is important to understand if subjects being treated with the immunomodulatory agents described have a less severe SARS-CoV-2 infection, as they are deemed some protection from their immunomodulatory treatment, or if they develop infections similar to non-immunocompromised patients. There is a huge unmet clinical need to advise patients responsibly about whether they should remain on their immunomodulatory treatment or not in light of Covid-19 infection. In this article we will discuss potential treatment options for SARS-CoV-2 using immunomodulatory drugs and at what stage of the condition they may be beneficial. Viable treatment options during the global coronavirus pandemic are a much-needed and an intensely active area of research.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Imunomodulação/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colchicina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/sangue , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Pessoa de Meia-Idade , Pandemias , Fatores de Risco , Fator de Necrose Tumoral alfa/antagonistas & inibidores
3.
Adv Exp Med Biol ; 1255: 221-230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949403

RESUMO

Monoclonal antibodies from human sources are being increasingly recognized as valuable options in many therapeutic areas. These antibodies can show exquisite specificity and high potency while maintaining a desirable safety profile, having been matured and tolerized within human patients. However, the discovery of these antibodies presents important challenges, since the B cells encoding therapeutic antibodies can be rare in a typical blood draw and are short-lived ex vivo. Furthermore, the unique pairing of VH and VL domains in each B cell contributes to specificity and function; therefore, maintaining antibody chain pairing presents a throughput limitation. This work will review the various approaches aimed at addressing these challenges with an eye to next-generation methods for high-throughput discovery from the human B-cell repertoire.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Descoberta de Drogas , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Humanos
4.
Oncology (Williston Park) ; 34(9): 370-376, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32965669

RESUMO

In an asymptomatic 77-yearold woman, former 55 packyears smoker, a routine X-ray showed a 45-mm superior left lobe lesion. A chest CT scan confirmed a 36-mm superior left lobe lesion and an aortic-pulmonary lymph node enlargement measuring 42 mm, suspicious for neoplasia. A PET-CT scan showed an elevated uptake in the primary lesion, in the aortic-pulmonary lymph node, and in the left hilar lymph node with a standardized uptake value - 40 and 4.3, respectively. CT-guided lung biopsy showed a lung squamous cell carcinoma. An endobronchial ultrasound-guided transbronchial needle aspiration for lymph-node staging was negative for lymph node spread. Brain MRI was negative. Final staging was determined to be a IIIA (T2bN2) squamous cell carcinoma of the lung.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Infecções por Coronavirus/diagnóstico , Neoplasias Pulmonares/terapia , Pneumonia Viral/diagnóstico , Pneumonia/diagnóstico , Idoso , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Betacoronavirus , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Quimiorradioterapia , Quimioterapia de Consolidação , Diagnóstico Diferencial , Feminino , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Paclitaxel/administração & dosagem , Pandemias , Pneumonia/induzido quimicamente
5.
Zhonghua Zhong Liu Za Zhi ; 42(8): 624-628, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867452

RESUMO

Small cell lung cancer (SCLC), a special type of lung cancer, is a highly malignant neuroendocrine tumor with strong invasiveness and rapid progression. SCLC is sensitive to radiotherapy and chemotherapy, so radiotherapy and chemotherapy have been the main first-line treatment of SCLC. However, it is easy to develop drug resistance after treatment. Therefore, the study of anti-angiogenic therapy has attracted more and more attention. At present, anti-angiogenic drugs mainly focus on four categories: monoclonal antibodies (such as bevacizumab), endogenous angiogenesis inhibitors (such as endostar), anti-angiogenic fusion protein (such as aflibercept) and small molecular tyrosine kinase inhibitors (such as anlotinib). There are still some bottlenecks in the research and clinical application of antiangiogenic drugs. It is the right direction to explore better combination therapy and effective dual-field and multi-target drugs.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/patologia , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
6.
Rinsho Ketsueki ; 61(8): 879-884, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908050

RESUMO

A 50-year-old woman diagnosed with surgically resected plasmacytoma of the ovaries and uterus presented with another plasmacytoma in the pancreas with positive uptake on positron emission tomography (PET) and massive right pleural effusion with plasma cell infiltration (myelomatous pleural effusion). After four courses of the bortezomib, lenalidomide, and dexamethasone regimen as induction therapy, partial response was achieved with reduced myelomatous pleural effusion and negative uptake on PET in the pancreatic plasmacytoma. However, soon after she received bortezomib and high-dose cyclophosphamide for peripheral blood stem cell harvesting, right myelomatous pleural effusion increased without signs of heart failure or infection. Because of the progressive nature of the disease, daratumumab was introduced as 2 courses of daratumumab, lenalidomide, and dexamethasone (DLd) regimen, after which she achieved complete response with disappearance of the pleural effusion. After autologous peripheral blood stem cell transplantation, she received an additional four courses of the DLd regimen as consolidation therapy. She maintained relapse-free survival for two years with maintenance therapy containing daratumumab and dose-reduced lenalidomide. Our case may suggest the usefulness of daratumumab before autologous peripheral stem cell transplantation for relapsed/refractory myelomatous pleural effusion.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Derrame Pleural , Protocolos de Quimioterapia Combinada Antineoplásica , Dexametasona , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Derrame Pleural/tratamento farmacológico
7.
Cochrane Database Syst Rev ; 9: CD013206, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32927498

RESUMO

BACKGROUND: Eczema is a common and chronic, relapsing, inflammatory skin disorder. It seriously impacts quality of life and economic outcomes, especially for those with moderate to severe eczema. Various treatments allow sustained control of the disease; however, their relative benefit remains unclear due to the limited number of trials directly comparing treatments. OBJECTIVES: To assess the comparative efficacy and safety of different types of systemic immunosuppressive treatments for moderate to severe eczema using NMA and to generate rankings of available systemic immunosuppressive treatments for eczema according to their efficacy and safety. SEARCH METHODS: We searched the following databases up to August 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. SELECTION CRITERIA: All randomised controlled trials (RCTs) of systemic immunosuppressive agents for moderate to severe atopic eczema when compared against placebo or any other eligible eczema treatment. DATA COLLECTION AND ANALYSIS: We synthesised data using pair-wise analysis and NMA to compare treatments and rank them according to their effectiveness. Effectiveness was assessed primarily by determining the proportion of participants who achieved at least 75% improvement in the Eczema Area and Severity Index (EASI75) and improvement in the Patient-Oriented Eczema Measure (POEM). Safety was evaluated primarily by considering the proportion of participants with serious adverse events (SAEs) and infection. We deemed short-term follow-up as ≤ 16 weeks and long-term follow-up as > 16 weeks. We assessed the certainty of the body of evidence from the NMA for these primary outcomes using six domains of CiNEMA grading. MAIN RESULTS: We included a total of 74 studies, with 8177 randomised participants. Approximately 55% of participants were male, with average age of 32 years (range 2 to 84 years), although age and gender were unreported for 419 and 902 participants, respectively. Most of the included trials were placebo controlled (65%), 34% were head-to-head studies (15% assessed the effects of different doses of the same drug), and 1% were multi-armed studies with both an active comparator and a placebo. All trials included participants with moderate to severe eczema, but 62% of studies did not separate data by severity; 38% of studies assessed only severe eczema. The total duration of included trials ranged from 2 weeks to 60 months, whereas treatment duration varied from a single dose (CIM331, KPL-716) to 60 months (methotrexate (MTX)). Seventy studies were available for quantitative synthesis; this review assessed 29 immunosuppressive agents from three classes of interventions. These included (1) conventional treatments, with ciclosporin assessed most commonly; (2) small molecule treatments, including phosphodiesterase (PDE)-4 inhibitors, tyrosine kinase inhibitors, and Janus kinase (JAK) inhibitors; and (3) biological treatments, including anti-CD31 receptors, anti-interleukin (IL)-22, anti-IL-31, anti-IL-13, anti-IL-12/23p40, anti-OX40, anti-TSLP, anti-CRTH2, and anti-immunoglobulin E (IgE) monoclonal antibodies, but most commonly dupilumab. Most trials (73) assessed outcomes at a short-term duration ranging from 2 to 16 weeks, whereas 33 trials assessed long-term outcomes, with duration ranging from 5 to 60 months. All participants were from a hospital setting. Fifty-two studies declared a source of funding, and of these, pharmaceutical companies funded 88%. We rated 37 studies as high risk; 21, unclear risk, and 16, low risk of bias, with studies most commonly at high risk of attrition bias. Network meta-analysis suggests that dupilumab ranks first for effectiveness when compared with other biological treatments. Dupilumab is more effective than placebo in achieving EASI75 (risk ratio (RR) 3.04, 95% confidence interval (CI) 2.51 to 3.69) and improvement in POEM score (mean difference 7.30, 95% CI 6.61 to 8.00) at short-term follow-up (high-certainty evidence). Very low-certainty evidence means we are uncertain of the effects of dupilumab when compared with placebo, in terms of the proportion of participants who achieve EASI75 (RR 2.59, 95% CI 1.87 to 3.60) at longer-term follow-up. Low-certainty evidence indicates that tralokinumab may be more effective than placebo in achieving short-term EASI75 (RR 2.54, 95% CI 1.21 to 5.34), but there was no evidence for tralokinumab to allow us to assess short-term follow-up of POEM or long-term follow-up of EASI75. We are uncertain of the effect of ustekinumab compared with placebo in achieving EASI75 (long-term follow-up: RR 1.17, 95% CI 0.40 to 3.45; short-term follow-up: RR 0.91, 95% CI 0.28 to 2.97; both very low certainty). We found no evidence on ustekinumab for the POEM outcome. We are uncertain whether other immunosuppressive agents that targeted our key outcomes influence the achievement of short-term EASI75 compared with placebo due to low- or very low-certainty evidence. Dupilumab and ustekinumab were the only immunosuppressive agents evaluated for longer-term EASI75. Dupilumab was the only agent evaluated for improvement in POEM during short-term follow-up. Low- to moderate-certainty evidence indicates a lower proportion of participants with SAEs after treatment with QAW039 and dupilumab compared to placebo during short-term follow-up, but low- to very low-certainty evidence suggests no difference in SAEs during short-term follow-up of other immunosuppressive agents compared to placebo. Evidence for effects of immunosuppressive agents on risk of any infection during short-term follow-up and SAEs during long-term follow-up compared with placebo was of low or very low certainty but did not indicate a difference. We did not identify differences in other adverse events (AEs), but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia. AUTHORS' CONCLUSIONS: Our findings indicate that dupilumab is the most effective biological treatment for eczema. Compared to placebo, dupilumab reduces eczema signs and symptoms in the short term for people with moderate to severe atopic eczema. Short-term safety outcomes from clinical trials did not reveal new safety concerns with dupilumab. Overall, evidence for the efficacy of most other immunosuppressive treatments for moderate to severe atopic eczema is of low or very low certainty. Given the lack of data comparing conventional with newer biological treatments for the primary outcomes, there remains high uncertainty for ranking the efficacy and safety of conventional treatments such as ciclosporin and biological treatments such as dupilumab. Most studies were placebo-controlled and assessed only short-term efficacy of immunosuppressive agents. Further adequately powered head-to-head RCTs should evaluate comparative long-term efficacy and safety of available treatments for moderate to severe eczema.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Eczema/tratamento farmacológico , Imunossupressores/uso terapêutico , Metanálise em Rede , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ustekinumab/uso terapêutico , Adulto Jovem
8.
N Engl J Med ; 383(12): 1149-1155, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32937047

RESUMO

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).


Assuntos
ADP-Ribosil Ciclase 1/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Plasmócitos/efeitos dos fármacos , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Creatinina/sangue , Creatinina/urina , Regulação para Baixo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Quimioterapia de Manutenção , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteinúria , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
9.
Brasília; s.n; 5 ago 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117760

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 11 artigos e 6 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Antivirais/uso terapêutico , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Metilprednisolona/uso terapêutico , Colchicina/uso terapêutico , Metotrexato/uso terapêutico , Estudos de Coortes , Interferons/uso terapêutico , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Oseltamivir/uso terapêutico , Células-Tronco Mesenquimais , Interferon alfa-2/uso terapêutico , Glucocorticoides/uso terapêutico , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico
10.
Brasília; s.n; 11 ago. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117979

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Avaliação da Tecnologia Biomédica , Ácido Ursodesoxicólico/uso terapêutico , Imunoglobulinas/uso terapêutico , Prednisolona/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Cloroquina/uso terapêutico , Estudos Transversais , Estudos de Coortes , Interferon-alfa/uso terapêutico , Tacrolimo/uso terapêutico , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Células-Tronco Mesenquimais , Lopinavir/uso terapêutico , Ácido Fólico/uso terapêutico , Meropeném/uso terapêutico , Hidroxicloroquina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ácido Micofenólico/uso terapêutico
11.
Medicine (Baltimore) ; 99(31): e21447, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756163

RESUMO

BACKGROUND: The comparative efficacy and safety of small molecule and biological agents in the treatment of psoriatic arthritis (PsA) remain unknown. OBJECTIVES: To compare the efficacy and safety of 14 small molecule and biological agents by network meta-analysis (NMA). METHODS: Relevant randomized controlled trials involving biological treatments for PsA were identified by searching PubMed, Cochrane Library, EMBASE, Web of Science, and Clinicaltrials.gov and by manual retrieval, up to June 2018. NMA was conducted with Stata 14.0 based on the frequentist method. Effect measures were odds ratios (ORs) with 95% confidence intervals (CIs). Intervention efficacy and safety were ranked according to the surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 30 studies involving 10,191 adult subjects were included. According to NMA, ≥ 20% improvement in modifed American College of Rheumatology response criteria (ACR20) response, Psoriasis Area and Severity Index 75 (PASI75) response, and serious adverse events rate (SAEs) were observed. In direct comparisons, most of the biologics performed better than placebo in terms of ACR20 response rate and PASI75 response rate. Additionally, all medicines were comparable to placebo in terms of SAEs except secukinumab. In terms of mixed comparisons, with regard to the ACR20 response, etanercept (ETN) and infliximab (IFX) were more effective than golimumab (GOL), with ORs of 3.33 (95% CI: 1.17-9.48) and 1.24 (95% CI: 0.61-2.52), respectively. For PASI75 response, IFX was superior to certolizumab pegol (OR = 10.08, 95% CI: 1.54-75.48). In addition, these medicines were comparable to each other in terms of SAEs. ETN and IFX were shown to have the most favorable SUCRA for achieving improved ACR20 and PASI75 responses, respectively, while ABT-122 exhibited the best safety according to the SUCRA for SAEs. Considering both the efficacy (ACR20, PASI75) and safety (SAEs), GOL, ETN, and IFX are the top 3 treatments. CONCLUSIONS AND IMPLICATIONS: Direct and indirect comparisons and integrated results suggested that the 3 anti- tumor necrosis factor -α biologics (GOL, ETN, and IFX) can be considered the best treatments for PsA after comprehensive consideration of efficacy and safety.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Biológicos/efeitos adversos , Estudos de Casos e Controles , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Índice de Gravidade de Doença , Resultado do Tratamento
14.
Science ; 369(6506): 936-942, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820119

RESUMO

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.


Assuntos
Antígenos de Neoplasias/imunologia , Bacteriófagos/imunologia , Streptococcus faecium ATCC 9790/virologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas da Cauda Viral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , Ciclofosfamida/uso terapêutico , Epitopos/imunologia , Fezes/virologia , Antígenos H-2/imunologia , Humanos , Camundongos , Neoplasias/dietoterapia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteínas da Cauda Viral/uso terapêutico
15.
Science ; 369(6506): 942-949, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820120

RESUMO

Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αß and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αß T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αß T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αß and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.


Assuntos
Antígenos CD/imunologia , Butirofilinas/antagonistas & inibidores , Butirofilinas/imunologia , Linfócitos Intraepiteliais/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Animais , Anticorpos Monoclonais/uso terapêutico , Antígenos CD/genética , Butirofilinas/genética , Feminino , Humanos , Imunoterapia/métodos , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
mSphere ; 5(4)2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32817460

RESUMO

Many coronavirus disease 2019 (COVID-19) patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but levels of tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) have not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients compared to healthy age- and gender-matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (P = 0.0209) in those who died than in survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients, with significantly (P = 0.0076) higher levels observed in patients who died than in survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited success in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses. The findings presented here demonstrate that LIGHT is a cytokine which may play an important role in COVID-19 patients presenting with acute respiratory distress syndrome (ARDS) and CRS and suggest that LIGHT neutralization may be beneficial to COVID-19 patients.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais/uso terapêutico , Betacoronavirus , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Hospitalização/estatística & dados numéricos , Humanos , Interleucina-6/imunologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Respiração Artificial/estatística & dados numéricos
19.
Neurology ; 95(7): e878-e888, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747522

RESUMO

OBJECTIVE: To evaluate fremanezumab quarterly or monthly vs placebo on health-related quality of life, health status, patients' global impression of change, and productivity in patients with chronic migraine (CM). METHODS: HALO CM was a double-blind, placebo-controlled trial in patients with CM. Patients were randomized 1:1:1 to treatment with fremanezumab quarterly (675 mg at baseline, placebo at weeks 4 and 8), fremanezumab monthly (225 mg at baseline, weeks 4 and 8), or placebo. This article assessed the effect of treatment with fremanezumab on health-related quality of life and productivity using the following prespecified assessments: the Migraine-Specific Quality of Life (MSQoL) questionnaire at baseline and weeks 4, 8, and 12; Patient Global Impression of Change (PGIC) questionnaire at weeks 4, 8, and 12; and EuroQoL 5-dimension, 5-response level (EQ-5D-5L) questionnaire and Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire at baseline and week 12. RESULTS: The full analysis set included 1,121 patients: 375 patients with quarterly dosing, 375 with monthly dosing, and 371 with placebo. Fremanezumab quarterly and monthly was associated with significant improvements over placebo in change from baseline mean scores in MSQoL domains (all, p < 0.05) to week 12. At week 12, fremanezumab also showed significant improvements in EQ-5D-5L visual analog scale (p < 0.05) and PGIC scores (p < 0.0001) as well as significant reductions from baseline in WPAI:GH scores (p < 0.01) and presenteeism (impairment while working; p < 0.05) vs placebo. CONCLUSIONS: Fremanezumab quarterly or monthly was associated with improvement over placebo in migraine-specific quality of life, overall health status, patients' global impression of change with treatment, and productivity in patients with CM. CLINICALTRIALSGOV IDENTIFIER: NCT02621931. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with CM, treatment with fremanezumab quarterly or monthly is associated with improvements in health-related quality of life and productivity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Dor Crônica/tratamento farmacológico , Transtornos de Enxaqueca/tratamento farmacológico , Qualidade de Vida , Adulto , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/complicações , Inquéritos e Questionários , Escala Visual Analógica , Desempenho Profissional
20.
N Engl J Med ; 383(8): 711-720, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32813947

RESUMO

BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).


Assuntos
Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/sangue , Criança , Método Duplo-Cego , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Infusões Intravenosas , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de LDL/metabolismo , Adulto Jovem
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