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1.
Oncoimmunology ; 10(1): 1859263, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33552684

RESUMO

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.

2.
J Clin Oncol ; : JCO2001814, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33513030

RESUMO

PURPOSE: In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS: MRD was assessed via next-generation sequencing (10-5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations. RESULTS: The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival. CONCLUSION: Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.

3.
IEEE Trans Biomed Eng ; PP2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33201806

RESUMO

OBJECTIVE: To develop a multi-channel device event segmentation and feature extraction algorithm that is robust to changes in data distribution. METHODS: We introduce an adaptive transfer learning algorithm to classify and segment events from non-stationary multi-channel temporal data. Using a multivariate hidden Markov model (HMM) and Fisher's linear discriminant analysis (FLDA) the algorithm adaptively adjusts to shifts in distribution over time. The proposed algorithm is unsupervised and learns to label events without requiring \textit{a priori} information about true event states. The procedure is illustrated on experimental data collected from a cohort in a human viral challenge (HVC) study, where certain subjects have disrupted wake and sleep patterns after exposure to a H1N1 influenza pathogen. RESULTS: Simulations establish that the proposed adaptive algorithm significantly outperforms other event classification methods. When applied to early time points in the HVC data the algorithm extracts sleep/wake features that are predictive of both infection and infection onset time. CONCLUSION: The proposed transfer learning event segmentation method is robust to temporal shifts in data distribution and can be used to produce highly discriminative event-labeled features for health monitoring. SIGNIFICANCE: Our integrated multisensor signal processing and transfer learning method is applicable to many ambulatory monitoring applications.

4.
Science ; 370(6513)2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33033192

RESUMO

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8+ T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure.


Assuntos
Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Ativação de Neutrófilo , Neutrófilos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios , Adolescente , Adulto , Animais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL1/farmacologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mucosa Nasal/patologia , Neutrófilos/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/patologia , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
5.
Ann Neurol ; 88(4): 747-758, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32740976

RESUMO

OBJECTIVE: We conducted a multisite, randomized, double-blinded, controlled trial to examine the effectiveness of a digital health intervention targeting the intrinsic regulation of goal-directed alertness in patients with chronic hemispatial neglect. METHODS: Forty-nine participants with hemispatial neglect, who demonstrated significant spatially biased attention after acquired brain injury, were randomly assigned to the experimental attention remediation treatment or the active control group. The participants engaged with the remotely administered interventions for 12 weeks. The primary outcome was spatial bias on the Posner cueing task (response time difference: left minus right target trials). Secondary outcomes included functional abilities (measured via the Catherine Bergego scale and Barthel index), spatial cognition, executive function, quality of life, and sleep. Assessments were conducted before and immediately after participation in the experimental intervention or control condition, and again after a 3-month no-contact period. RESULTS: Compared with the active control group, the intervention group exhibited a significant improvement in the primary outcome, a reduction in spatially biased attention on the Posner cueing task (p = 0.010, Cohen's d = 0.96), in addition to significant improvements in functional abilities as measured on the Catherine Bergego and Barthel indices (p = 0.027, Cohen's d = 0.24). INTERPRETATION: Our results demonstrate that our attention training program was effective in improving the debilitating attention deficits common to hemispatial neglect. This benefit generalized to improvements in real-world functional abilities. This safe, highly scalable, and self-administered treatment for hemispatial neglect might serve as a useful addition to the existing standard of care. ANN NEUROL 2020;88:747-758.

6.
Clin Lymphoma Myeloma Leuk ; 20(8): 509-518, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32482541

RESUMO

BACKGROUND: In the phase III CASTOR study in relapsed or refractory multiple myeloma, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone. Outcomes after 40.0 months of median follow-up are discussed. PATIENTS AND METHODS: Eligible patients had received ≥ 1 line of treatment and were administered bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for 8 cycles with or without daratumumab (16 mg/kg) until disease progression. RESULTS: Of 498 patients in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247), 47% had 1 prior line of treatment (1PL; D-Vd, n = 122; Vd, n = 113). Median progression-free survival (PFS) was significantly prolonged with D-Vd versus Vd in the ITT population (16.7 vs. 7.1 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.25-0.40; P < .0001) and the 1PL subgroup (27.0 vs. 7.9 months; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). In lenalidomide-refractory patients, the median PFS was 7.8 versus 4.9 months (HR, 0.44; 95% CI, 0.28-0.68; P = .0002) for D-Vd (n = 60) versus Vd (n = 81). Minimal residual disease (MRD)-negativity rates (10-5) were greater with D-Vd versus Vd (ITT: 14% vs. 2%; 1PL: 20% vs. 3%; both P < .0001). PFS2 was significantly prolonged with D-Vd versus Vd (ITT: HR, 0.48; 95% CI, 0.38-0.61; 1PL: HR, 0.35; 95% CI, 0.24-0.51; P < .0001). No new safety concerns were observed. CONCLUSION: After 3 years, D-Vd maintained significant benefits in patients with relapsed or refractory multiple myeloma with a consistent safety profile. D-Vd provided the greatest benefit at first relapse and increased MRD-negativity rates.

7.
Leukemia ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457357

RESUMO

CD38-targeted antibody, daratumumab, is approved for the treatment of multiple myeloma (MM). Phase 1/2 studies GEN501/SIRIUS revealed a novel immunomodulatory mechanism of action (MOA) of daratumumab that enhanced the immune response, reducing natural killer (NK) cells without affecting efficacy or safety. We further evaluated daratumumab's effects on immune cells in whole blood samples of relapsed/refractory MM patients from both treatment arms of the phase 3 POLLUX study (lenalidomide/dexamethasone [Rd] or daratumumab plus Rd [D-Rd]) at baseline (D-Rd, 40; Rd, 45) and after 2 months on treatment (D-Rd, 31; Rd, 33) using cytometry by time-of-flight. We confirmed previous reports of NK cell reduction with D-Rd. Persisting NK cells were phenotypically distinct, with increased expression of HLA-DR, CD69, CD127, and CD27. The proportion of T cells increased preferentially in deep responders to D-Rd, with a higher proportion of CD8+ versus CD4+ T cells. The expansion of CD8+ T cells correlated with clonality, indicating generation of adaptive immune response with D-Rd. D-Rd resulted in a higher proportion of effector memory T cells versus Rd. D-Rd reduced immunosuppressive CD38+ regulatory T cells. This study confirms daratumumab's immunomodulatory MOA in combination with immunomodulatory drugs and provides further insight into immune cell changes and activation status following daratumumab-based therapy.

8.
BMC Bioinformatics ; 21(1): 98, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143562

RESUMO

BACKGROUND: Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies. RESULTS: Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data. Evaluation of CNV Radar in a public multiple myeloma dataset demonstrated that CNV Radar was able to detect a variety of CNVs associated with risk of progression, and we observed > 70% concordance with fluorescence in situ hybridization (FISH) results. Compared to other CNV callers, CNV Radar showed high sensitivity and specificity. Similar results were observed when comparing CNV Radar calls to single nucleotide polymorphism array results from acute myeloid leukemia and prostate cancer datasets available on TCGA. More importantly, CNV Radar demonstrated its utility in the clinical trial setting: in POLLUX and CASTOR, two phase 3 studies in patients with relapsed or refractory multiple myeloma, we observed a high concordance rate with FISH for del17p, a risk defining CNV event (88% in POLLUX and 90% in CASTOR), therefore allowing for efficacy assessments in clinically relevant disease subgroups. Our case studies also showed that CNV Radar is capable of detecting abnormalities such as copy-neutral loss of heterozygosity that elude other approaches. CONCLUSIONS: We demonstrated that CNV Radar is more sensitive than other CNV detection methods, accurately detects clinically important cytogenetic events, and allows for further interrogation of novel disease biology. Overall, CNV Radar exhibited high concordance with standard methods such as FISH, and its success in the POLLUX and CASTOR clinical trials demonstrated its potential utility for informing clinical and therapeutic decisions.


Assuntos
Variações do Número de Cópias de DNA , Leucemia Mieloide Aguda/genética , Neoplasias da Próstata/genética , Software , Algoritmos , Área Sob a Curva , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Curva ROC
9.
Leukemia ; 34(7): 1875-1884, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32001798

RESUMO

In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1-21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35-0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10-5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31-0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42-0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Idoso , Anticorpos Monoclonais/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Masculino , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Talidomida/administração & dosagem
10.
J Sex Res ; 57(6): 681-708, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32077326

RESUMO

In the U.S., sexual minority men (SMM) are disproportionately affected by HIV. Interventions are needed to increase HIV prevention and treatment behaviors, especially among syndemically exposed SMM. In recent years, researchers have created and tested combination behavioral interventions co-targeting syndemics and HIV-related health behaviors. We evaluated that literature via systematic review and meta-analysis, identifying 44 trials targeting mental health symptoms, alcohol use, and drug use, as well as sexual risk behavior, antiretroviral adherence, and healthcare engagement. For the randomized controlled trials, we computed between-group, pre-post effect sizes and tested them via random-effects models. Results supported the efficacy of combined interventions with significant, small, positive effects for improving mental health and reducing substance use (d = .20, CIs: 0.12, .29), and reducing sexual risk behavior and improving antiretroviral adherence (d = .16, CIs: .03, .30). Stratification analyses indicate that longer (9+ sessions) and individual (vs. group) interventions resulted in stronger effects on syndemic but not health behavior outcomes. Intervention developers should attend to intervention intensity and format. More evidence is needed about the importance of additional factors, such as novel intervention targets and cultural tailoring, as well as broadening the focus to multi-level interventions to address both interpersonal and structural mechanisms of change.

11.
Haematologica ; 105(4): 1032-1041, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31296574

RESUMO

CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20dim FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.

12.
Haematologica ; 105(2): 468-477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31221782

RESUMO

The phase 3 POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival versus lenalido-mide/dexamethasone (median: 28.9 versus 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; P=0.0042) and increased overall response rate (93.1% versus 76.5%; P=0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 versus 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; P=0.0022) and increased overall response rate (95.0% versus 78.8%; P=0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of daratumumab was largely consistent with the overall populations.

13.
J Clin Invest ; 130(1): 523-538, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31815739

RESUMO

BACKGROUNDRespiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung.METHODSHealthy adult volunteers were inoculated i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding.RESULTSActivated CD4+ T cell frequencies in bronchoalveolar lavage correlated strongly with local C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3' end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (F-EFY) epitope restricted to HLA-DR4, -DR9, and -DR11 (combined allelic frequency: 15% in Europeans) and G-DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved.CONCLUSIONSHuman infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of Trm recognizing novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.TRIAL REGISTRATIONClinicalTrials.gov NCT02755948.FUNDINGMedical Research Council, Wellcome Trust, National Institute for Health Research.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Mapeamento de Epitopos , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Epitopos de Linfócito T , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/patologia
14.
Front Immunol ; 10: 2625, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787986

RESUMO

Influenza A virus infection is a global health threat to livestock and humans, causing substantial mortality and morbidity. As both pigs and humans are readily infected with influenza viruses of similar subtype, the pig is a robust and appropriate model for investigating swine and human disease. We evaluated the efficacy of the human cold-adapted 2017-2018 quadrivalent seasonal LAIV in pigs against H1N1pdm09 challenge. LAIV immunized animals showed significantly reduced viral load in nasal swabs. There was limited replication of the H1N1 component of the vaccine in the nose, a limited response to H1N1 in the lung lymph nodes and a low H1N1 serum neutralizing titer. In contrast there was better replication of the H3N2 component of the LAIV, accompanied by a stronger response to H3N2 in the tracheobronchial lymph nodes (TBLN). Our data demonstrates that a single administration of human quadrivalent LAIV shows limited replication in the nose and induces detectable responses to the H1N1 and H3N2 components. These data suggest that pigs may be a useful model for assessing LAIV against influenza A viruses.


Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza , Infecções por Orthomyxoviridae/prevenção & controle , Vacinas Atenuadas , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Temperatura Baixa , Citocinas/imunologia , Feminino , Células HEK293 , Humanos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Linfonodos/imunologia , Linfonodos/virologia , Nariz/virologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Estações do Ano , Suínos
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
16.
N Engl J Med ; 380(22): 2104-2115, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31141632

RESUMO

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%). CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão
18.
Am J Respir Crit Care Med ; 200(4): 481-492, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30753101

RESUMO

Rationale: Needle-free intranasal vaccines offer major potential advantages, especially against pathogens entering via mucosal surfaces. As yet, there is no effective vaccine against respiratory syncytial virus (RSV), a ubiquitous pathogen of global importance that preferentially infects respiratory epithelial cells; new strategies are urgently required.Objectives: Here, we report the safety and immunogenicity of a novel mucosal RSV F protein vaccine linked to an immunostimulatory bacterium-like particle (BLP).Methods: In this phase I, randomized, double-blind, placebo-controlled trial, 48 healthy volunteers, aged 18-49 years, were randomly assigned to receive placebo or SynGEM (low or high dose) intranasally by prime-boost administration. The primary outcome was safety and tolerability, with secondary objectives assessing virus-specific immunogenicity.Measurements and Main Results: There were no significant differences in adverse events between placebo and vaccinated groups. SynGEM induced systemic plasmablast responses and significant, durable increases in RSV-specific serum antibody in healthy, seropositive adults. Volunteers given low-dose SynGEM (140 µg F, 2 mg BLP) required a boost at Day 28 to achieve plateau responses with a maximum fold change of 2.4, whereas high-dose recipients (350 µg F, 5 mg BLP) achieved plateau responses with a fold change of 1.5 after first vaccination that remained elevated up to 180 days after vaccination, irrespective of further boosting. Palivizumab-like antibodies were consistently induced, but F protein site ∅-specific antibodies were not detected, and virus-specific nasal IgA responses were heterogeneous, with the strongest responses in individuals with lower pre-existing antibody levels.Conclusions: SynGEM is thus the first nonreplicating intranasal RSV subunit vaccine to induce persistent antibody responses in human volunteers.Clinical trials registered with www.clinicaltrials.gov (NCT02958540).


Assuntos
Anticorpos Antivirais/imunologia , Imunogenicidade da Vacina , Imunoglobulina A/imunologia , Mucosa Nasal/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Administração Intranasal , Adolescente , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Imunização Secundária , Masculino , Pessoa de Meia-Idade , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Adulto Jovem
19.
Cytometry A ; 95(3): 279-289, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30536810

RESUMO

Daratumumab is a CD38-targeted human monoclonal antibody with direct anti-myeloma cell mechanisms of action. Flow cytometry in relapsed and/or refractory multiple myeloma (RRMM) patients treated with daratumumab revealed cytotoxic T-cell expansion and reduction of immune-suppressive populations, suggesting immune modulation as an additional mechanism of action. Here, we performed an in-depth analysis of the effects of daratumumab on immune-cell subpopulations using high-dimensional mass cytometry. Whole-blood and bone-marrow baseline and on-treatment samples from RRMM patients who participated in daratumumab monotherapy studies (SIRIUS and GEN501) were evaluated with high-throughput immunophenotyping. In daratumumab-treated patients, the intensity of CD38 marker expression decreased on many immune cells in SIRIUS whole-blood samples. Natural killer (NK) cells were depleted with daratumumab, with remaining NK cells showing increased CD69 and CD127, decreased CD45RA, and trends for increased CD25, CD27, and CD137 and decreased granzyme B. Immune-suppressive population depletion paralleled previous findings, and a newly observed reduction in CD38+ basophils was seen in patients who received monotherapy. After 2 months of daratumumab, the T-cell population in whole-blood samples from responders shifted to a CD8 prevalence with higher granzyme B positivity (P = 0.017), suggesting increased killing capacity and supporting monotherapy-induced CD8+ T-cell activation. High-throughput cytometry immune profiling confirms and builds upon previous flow cytometry data, including comparable CD38 marker intensity on plasma cells, NK cells, monocytes, and B/T cells. Interestingly, a shift toward cytolytic granzyme B+ T cells was also observed and supports adaptive responses in patients that may contribute to depth of response. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Basófilos/citologia , Basófilos/efeitos dos fármacos , Basófilos/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Citometria de Fluxo , Granzimas/metabolismo , Humanos , Imunofenotipagem , Células Matadoras Naturais/citologia , Mieloma Múltiplo/sangue , Mieloma Múltiplo/metabolismo , Recidiva
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