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2.
Anticancer Res ; 39(9): 4987-4993, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519605

RESUMO

BACKGROUND/AIM: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment. PATIENTS AND METHODS: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history. RESULTS: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients. CONCLUSION: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Docetaxel/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
3.
Anticancer Res ; 39(9): 5165-5170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519629

RESUMO

BACKGROUND/AIM: Daratumumab is a promising novel agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its efficacy and toxicity profiles in real-world patients, especially in the Asian population. PATIENTS AND METHODS: This was a multicenter, retrospective, longitudinal cohort study set between January 2017 and April 2019. We collected and analyzed clinical and survival data of 21 patients treated with daratumumab monotherapy. All patients were previously exposed to proteasome inhibitors and immunomodulatory drugs. RESULTS: The overall response rate was 42.1%, including one complete remission (4.8%) and three very good partial responses (14.3%). The cycles of daratumumab delivered were three (range=1-10 cycles) and the median progression-free survival was 6 months, while the overall survival was not reached. Infusion reaction was observed in nine patients (42.9%), and one discontinued permanently. Fatigue was the most common adverse event (52.4%), and there were five cases of documented infection during daratumumab treatment, two of them leading to the death of the patient. CONCLUSION: Daratumumab monotherapy showed fairly promising activity with modest tolerance in heavily treated Asian RRMM patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Ásia , Linhagem Celular Tumoral , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
4.
Lancet ; 394(10200): 793-804, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31478503

RESUMO

Antibody-drug conjugates (ADCs) are immunoconjugates comprised of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. The ADC is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, five ADCs have received market approval and over 100 are being investigated in various stages of clinical development. In this Therapeutics paper, we review recent clinical experience with the approved ADCs and other promising late-stage candidates on the horizon, following an overview of the biology and chemistry of ADCs and how the individual components of an ADC (antibody [or target], linker and conjugation chemistry, and cytotoxic payload) influence its activity. We briefly discuss opportunities for enhancing ADC efficacy, drug resistance, and future perspectives for this novel antibody-based molecular platform, which has great potential to make a paradigm shift in cancer chemotherapy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Imunoconjugados , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia
5.
Pharm Res ; 36(10): 145, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396764

RESUMO

PURPOSE: The immediate plasma metabolism and development of chemo-resistance (single agent) severely hampers the clinical effectiveness of Sorafenib (SRF) in liver cancer therapy. MicroRNA27a inhibition is a promising biological strategy for breast cancer therapy. METHODS: In this study, we aimed to prepare SRF and anti-miRNA27a-loaded anti-GPC3 antibody targeted lipid nanoparticles to enhance the therapeutic efficacy against liver cancers. In this study, we have employed a unique cationic switchable lipid (CSL) as a mean to encapsulate miRNA as well as to confer pH-responsiveness to the nanocarrier system. RESULTS: The G-S27LN was nanosized and offered a pH-responsive release of SRF from the carrier system and we have demonstrated the specific affinity of G-S27LN towards the GPC3-overexpressed HepG2 cancer cells. Anti-microRNA27a significantly increased the protein expression of FOXO1 and PPAR-γ which are crucial components involved in proliferation and apoptosis of tumor cells. Combination of SRF and anti-miRNA27a (G-S27LN) resulted in significantly lower cell viability with a marked increase in the apoptosis cell proportion compared to that of free SRF indicating the synergistic anticancer effect. Animal studies in liver cancer xenograft model demonstrated significant suppression of tumor burden, reduced tumor cell and elevated TUNEL positive apoptosis with no toxicity concerns in animals treated with G-S27LN formulation. CONCLUSION: The CSL-based G-S27LN efficiently co-delivered anti-microRNA27a and SRF and therefore represents a promising therapy to treat liver cancer. This study also brings forth a platform strategy for the effective treatment of number of other advanced cancers.


Assuntos
Antagomirs/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Glipicanas/imunologia , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , MicroRNAs/imunologia , Nanopartículas/química , Sorafenibe/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Sinergismo Farmacológico , Proteína Forkhead Box O1/metabolismo , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Camundongos Nus , PPAR gama/metabolismo , Fosforilcolina/química , Polietilenoglicóis/química
6.
Einstein (Sao Paulo) ; 17(4): eRC4599, 2019 Jul 10.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31291386

RESUMO

Case report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Imunossupressores/administração & dosagem , Adolescente , Brasil , Feminino , Humanos , Imunossupressão , Injeções Subcutâneas , Interleucina-13 , Interleucina-4 , Qualidade de Vida , Índice de Gravidade de Doença
7.
N Engl J Med ; 381(2): 132-141, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31291515

RESUMO

BACKGROUND: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache. METHODS: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month. The primary end point was the mean change from baseline in the weekly frequency of cluster headache attacks across weeks 1 through 3 after receipt of the first dose. The key secondary end point was the percentage of patients who had a reduction from baseline of at least 50% in the weekly frequency of cluster headache attacks at week 3. Safety was also assessed. RESULTS: Recruitment was halted before the trial reached the planned sample size of 162 because too few volunteers met the eligibility criteria. Of 106 enrolled patients, 49 were randomly assigned to receive galcanezumab and 57 to receive placebo. The mean (±SD) number of cluster headache attacks per week in the baseline period was 17.8±10.1 in the galcanezumab group and 17.3±10.1 in the placebo group. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week; 95% confidence interval, 0.2 to 6.7; P = 0.04). The percentage of patients who had a reduction of at least 50% in headache frequency at week 3 was 71% in the galcanezumab group and 53% in the placebo group. There were no substantial between-group differences in the incidence of adverse events, except that 8% of the patients in the galcanezumab group had injection-site pain. CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of 300 mg once monthly reduced the weekly frequency of attacks of episodic cluster headache across weeks 1 through 3 after the initial injection, as compared with placebo. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT02397473.).


Assuntos
Analgésicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Cefaleia Histamínica/prevenção & controle , Adulto , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos/uso terapêutico
8.
Lancet ; 394(10198): 576-586, 2019 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-31280967

RESUMO

BACKGROUND: Psoriasis is an autoimmune disease that affects approximately 100 million people worldwide, and is a disease that can be ameliorated by anti-cytokine treatment. We aimed to compare the efficacy and safety of risankizumab with adalimumab in patients with moderate-to-severe plaque psoriasis. METHODS: IMMvent was a phase 3, randomised, double-blind, active-comparator-controlled trial completed at 66 clinics in 11 countries. Eligible patients were aged 18 years or older with moderate-to-severe chronic plaque psoriasis. Patients were randomly assigned 1:1 using interactive response technology to receive 150 mg risankizumab subcutaneously at weeks 0 and 4 or 80 mg adalimumab subcutaneously at randomisation, then 40 mg at weeks 1, 3, 5, and every other week thereafter during a 16-week double-blind treatment period (part A). For weeks 16-44 (part B), adalimumab intermediate responders were re-randomised 1:1 to continue 40 mg adalimumab or switch to 150 mg risankizumab. In part A, participants and investigators were masked to study treatment. Randomisation was stratified by weight and previous tumour necrosis factor inhibitor exposure. Co-primary endpoints in part A were a 90% improvement from baseline (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16, and for part B was PASI 90 at week 44 (non-responder imputation). Efficacy analyses were done in the intention-to-treat population and safety analyses were done in the safety population (all patients who received at least one dose of study drug or placebo). This study is registered with ClinicalTrials.gov, number NCT02694523. FINDINGS: Between March 31, 2016, and Aug 24, 2017, 605 patients were randomly assigned to receive either risankizumab (n=301, 50%) or adalimumab (n=304, 50%). 294 (98%) of patients in the risankizumab group and 291 (96%) in the adalimumab group completed part A, and 51 (96%) of 53 patients re-randomised to risankizumab and 51 (91%) of 56 patients re-randomised to continue adalimumab completed part B. At week 16, PASI 90 was achieved in 218 (72%) of 301 patients given risankizumab and 144 (47%) of 304 patients given adalimumab (adjusted absolute difference 24·9% [95% CI 17·5-32·4]; p<0·0001), and sPGA scores of 0 or 1 were achieved in 252 (84%) patients given risankizumab and 252 (60%) patients given adalimumab (adjusted absolute difference 23·3% [16·6-30·1]; p<0·0001). In part B, among adalimumab intermediate responders, PASI 90 was achieved by 35 (66%) of 53 patients switched to risankizumab and 12 (21%) of 56 patients continuing adalimumab (adjusted absolute difference 45·0% [28·9-61·1]; p<0·0001) at week 44. Adverse events were reported in 168 (56%) of 301 patients given risankizumab and 179 (57%) of 304 patients given adalimumab in part A, and among adalimumab intermediate responders, adverse events were reported in 40 (75%) of 53 patients who switched to risankizumab and 37 (66%) of 56 patients who continued adalimumab in part B. INTERPRETATION: Risankizumab showed significantly greater efficacy than adalimumab in providing skin clearance in patients with moderate-to-severe plaque psoriasis. No additional safety concerns were identified for patients who switched from adalimumab to risankizumab. Treatment with risankizumab provides flexibility in the long-term treatment of psoriasis. FUNDING: AbbVie and Boehringer Ingelheim.


Assuntos
Adalimumab/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Adalimumab/efeitos adversos , Adulto , Anticorpos Monoclonais/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade
9.
J Cancer Res Clin Oncol ; 145(9): 2365-2373, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280347

RESUMO

AIMS AND METHODS: This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a "real-life" setting. RESULTS: From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m2 and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02-5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2-40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6-6.8) and mOS was 8.7 months (95% CI 7.3-11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01-2.82), p = 0.04] [HR = 1.97 (95% CI 1.12-3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01-2.83), p = 0.04] [HR = 2.08 (95% CI 1.17-3.70), p = 0.01]. CONCLUSION: Efficacy of ramucirumab is confirmed in this "real-life" analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Neoplasias Gástricas/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Quimioterapia Adjuvante , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento , Perda de Peso/fisiologia
10.
Medicine (Baltimore) ; 98(25): e15944, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232925

RESUMO

OBJECTIVE: To test the safety of ublituximab, a B cell depleting agent, as add-on therapy in the acute treatment of relapses of neuromyelitis optica spectrum disorder. METHODS: We conducted an open-label phase 1b safety and proof-of-concept trial in 5 subjects with aquaporin-4 (AQP4)-immunoglobulin G (IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily intravenous methylprednisolone, we infused a single dose of 450 mg of ublituximab within 5 days of relapse onset. The primary outcome measure was safety, and the secondary efficacy measures included change in Expanded Disability Status Scale (EDSS), durability of remission and B cell counts. RESULTS: Five NMOSD subjects were enrolled, 4 of whom presented with acute transverse myelitis and 1 with acute optic neuritis. Ublituximab proved to be safe in all 5 NMOSD subjects, with no serious adverse events recorded. There were no opportunistic infections in any of the subjects; however, 1 subject experienced a transient leukopenia. EDSS scores dropped from a median of 6.5 on admission to 4.0 on 90-day follow up. Two subjects did not achieve total B cell depletion and relapsed within 3 months. CONCLUSIONS: Ublituximab is a safe add-on therapy for NMOSD patients presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit on durability of remission when B cell depletion is achieved. A placebo-controlled trial is necessary to confirm these findings. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with NMOSD with acute transverse myelitis or optic neuritis, ublituximab is safe and may improve neurological outcome.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20 , Metilprednisolona/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metilprednisolona/administração & dosagem , Neuromielite Óptica/patologia , Projetos Piloto , Recidiva , Resultado do Tratamento
11.
Nat Commun ; 10(1): 2699, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221976

RESUMO

Human cytomegalovirus (CMV) causes a wide array of disease to diverse populations of immune-compromised individuals. Thus, a more comprehensive understanding of how CMV enters numerous host cell types is necessary to further delineate the complex nature of CMV pathogenesis and to develop targeted therapeutics. To that end, we establish a vaccination strategy utilizing membrane vesicles derived from epithelial cells to generate a library of monoclonal antibodies (mAbs) targeting cell surface proteins in their native conformation. A high-throughput inhibition assay is employed to screen these antibodies for their ability to limit infection, and mAbs targeting CD46 are identified. In addition, a significant reduction of viral proliferation in CD46-KO epithelial cells confirms a role for CD46 function in viral dissemination. Further, we demonstrate a CD46-dependent entry pathway of virus infection in trophoblasts, but not in fibroblasts, highlighting the complexity of CMV entry and identifying CD46 as an entry factor in congenital infection.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Proteína Cofatora de Membrana/imunologia , Internalização do Vírus , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/imunologia , Linhagem Celular , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/virologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Fibroblastos/imunologia , Fibroblastos/virologia , Técnicas de Inativação de Genes , Humanos , Proteína Cofatora de Membrana/genética , RNA Interferente Pequeno/metabolismo , Trofoblastos/imunologia , Trofoblastos/virologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
12.
Nat Med ; 25(6): 929-935, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171876

RESUMO

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Azetidinas/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Estudos de Coortes , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/secundário , Mutação , Piperidinas/administração & dosagem , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/administração & dosagem
14.
Nat Commun ; 10(1): 2782, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239444

RESUMO

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Anticorpos Monoclonais/administração & dosagem , Melanoma/enzimologia , Melanoma/terapia , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Desmetilação , Feminino , Humanos , Imunoterapia , Melanoma/genética , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Lancet ; 394(10192): 29-38, 2019 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171419

RESUMO

BACKGROUND: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. METHODS: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21-2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10-5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33-0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23-0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). INTERPRETATION: D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. FUNDING: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Talidomida/administração & dosagem , Talidomida/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
17.
Rev Assoc Med Bras (1992) ; 65(4): 493-508, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31066801

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Etanercepte/administração & dosagem , Fatores Imunológicos/administração & dosagem , Psoríase/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Brasil , Tomada de Decisão Clínica , Etanercepte/efeitos adversos , Humanos , Fatores Imunológicos/efeitos adversos , Psoríase/patologia , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
18.
Rev Assoc Med Bras (1992) ; 65(4): 530-534, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31066805

RESUMO

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Imunossupressores/administração & dosagem , Psoríase/tratamento farmacológico , Acitretina/administração & dosagem , Acitretina/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Brasil , Tomada de Decisão Clínica , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Psoríase/patologia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
19.
Expert Opin Drug Metab Toxicol ; 15(6): 517-520, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31104515

RESUMO

Background: To date, there is the strong need to compare the efficacy across the monoclonal antibodies (mAbs) approved to treat severe asthma. Research design and method: A quantitative synthesis has been performed to compare the impact of omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and placebo on the risk of exacerbation and change in forced expiratory flow in 1 s (FEV1) in severe asthmatic patients. Results: All the investigated mAbs were more effective than placebo in reducing the risk of exacerbation and improving lung function. Dupilumab showed a general superiority compared to the other mAbs, as it significantly reduced the risk of exacerbation vs. omalizumab, and significantly improved FEV1 when compared to omalizumab, mepolizumab, and benralizumab. The overall-marked placebo effect indicates that a better adherence to drug regimens in the context of RCTs may lead to noteworthy improvement in the clinical condition of severe asthmatic patients. Conclusions: Further extensive meta-analyses are needed to identify the factors influencing the efficacy profile of mAbs in severe asthma. This may also permit to identify the profile of patients that are specifically responsive to either anti-IgE, anti-IL-4Rα, anti-IL-5, or anti-IL-5Rα mAbs.


Assuntos
Antiasmáticos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Antiasmáticos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Asma/fisiopatologia , Volume Expiratório Forçado , Humanos , Adesão à Medicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
20.
J Headache Pain ; 20(1): 49, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060490

RESUMO

BACKGROUND: Migraine is a major public health issue associated with significant morbidity, considerable negative impact on quality of life, and significant socioeconomic burden. Preventive treatments are required to reduce the occurrence and the severity of acute attacks and to minimize the use of abortive medications and the associate risk of drug-related adverse events, as well as the onset of medication-overuse headache and chronification of migraine. We performed a review of all available evidence on the safety and efficacy of monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor for the preventive treatment of migraine to provide evidence-based guidance on their use in clinical practice. Monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are mechanism-specific drugs for the preventive treatment of migraine. Double-blind randomized clinical trials have shown that monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are effective across all the spectrum of migraine patients who require prevention and have a good safety and tolerability profile. Nevertheless, high costs limit the affordability of those drugs at the moment. CONCLUSIONS: Specificity, long half-life, efficacy, tolerability, and ease of use make monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor an appealing treatment option for migraine prevention. Optimal strategies to manage treatment over time still need to be clarified with real-life data.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/metabolismo , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , Saúde Pública/métodos , Qualidade de Vida/psicologia
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