RESUMEN
BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
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Antineoplásicos Inmunológicos , Antígeno de Maduración de Linfocitos B , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Lenalidomida/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Síndromes de Neurotoxicidad , Supervivencia sin Progresión , Antígeno de Maduración de Linfocitos B/inmunología , Inmunoterapia Adoptiva/métodos , Antineoplásicos Inmunológicos/uso terapéutico , Resistencia a AntineoplásicosRESUMEN
Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.
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Linfocitos T CD8-positivos/inmunología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Transcripción Genética/inmunología , Enfermedad Aguda , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/inmunología , Variación Genética/inmunología , Hepacivirus/fisiología , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Rituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials. METHODS: In a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment). RESULTS: Of the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, -1595 mg; 95% CI, -2838 to -353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was -8.87 points and -6.00 points, respectively (difference, -2.87 points; 95% CI, -4.58 to -1.17; P = 0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group. CONCLUSIONS: Rituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann-La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.).
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Ácido Micofenólico/uso terapéutico , Pénfigo/tratamiento farmacológico , Rituximab/uso terapéutico , Administración Oral , Adulto , Anciano , Método Doble Ciego , Quimioterapia Combinada , Femenino , Glucocorticoides/administración & dosificación , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Inducción de Remisión , Rituximab/efectos adversosRESUMEN
BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.
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Piodermia Gangrenosa , Adulto , Humanos , Resultado del Tratamiento , Piodermia Gangrenosa/diagnóstico , Estudios Prospectivos , Evaluación de Resultado en la Atención de Salud , Dolor , Técnica Delphi , Proyectos de InvestigaciónRESUMEN
PURPOSE OF REVIEW: Genetic therapies made a significant impact to the clinical course of patients with spinal muscular atrophy and Duchenne muscular dystrophy. Clinicians and therapists who care for these patients want to know the changes in respiratory sequelae and implications for clinical care for treated patients. RECENT FINDINGS: Different genetic therapy approaches have been developed to replace the deficient protein product in spinal muscular atrophy and Duchenne muscular dystrophy. The natural history of these conditions needed to be understood in order to design clinical trials. Respiratory parameters were not the primary outcome measures for the clinical trials. The impact of these therapies is described in subsequent clinical trial reports or real-world data. SUMMARY: Genetic therapies are able to stabilize or improve the respiratory sequelae in patients with spinal muscular atrophy and Duchenne muscular dystrophy. Standardized reporting of these outcomes is needed to help inform the future revisions of clinical standards of care and practice guidelines.
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Terapia Genética , Distrofia Muscular de Duchenne , Humanos , Terapia Genética/métodos , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/genética , Niño , Atrofia Muscular Espinal/terapia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment. METHODS: Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks. RESULTS: The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log10 IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets. CONCLUSION: Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48. GOV IDENTIFIER: NCT03491553. IMPACT AND IMPLICATIONS: The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.
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Antivirales , Hepatitis B Crónica , Receptor Toll-Like 8 , Humanos , Antivirales/uso terapéutico , Citocinas , Antígenos e de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Hepatitis B Crónica/tratamiento farmacológico , Receptor Toll-Like 8/agonistas , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
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Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor Toll-Like 8/agonistas , Adulto , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Cefalea/inducido químicamente , Hepatitis B Crónica/sangre , Hexanoles/farmacología , Humanos , Proteína Antagonista del Receptor de Interleucina 1/sangre , Subunidad p40 de la Interleucina-12/sangre , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Pirimidinas/farmacología , Respuesta Virológica SostenidaRESUMEN
Soil is a scattering medium that inhibits imaging of plant-microbial-mineral interactions that are essential to plant health and soil carbon sequestration. However, optical imaging in the complex medium of soil has been stymied by the seemingly intractable problems of scattering and contrast. Here, we develop a wavefront shaping method based on adaptive stochastic parallel gradient descent optimization with a Hadamard basis to focus light through soil mineral samples. Our approach allows a sparse representation of the wavefront with reduced dimensionality for the optimization. We further divide the used Hadamard basis set into subsets and optimize a certain subset at once. Simulation and experimental optimization results demonstrate our method has an approximately seven times higher convergence rate and overall better performance compared to that with optimizing all pixels at once. The proposed method can benefit other high-dimensional optimization problems in adaptive optics and wavefront shaping.
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Óptica y Fotónica , Suelo , Simulación por Computador , Imagen ÓpticaRESUMEN
PURPOSE: We conducted a randomized, double-blind, vehicle-controlled clinical trial to investigate the use of a new proprietary hyaluronan (HA) formulation for the prevention of acute skin toxicity in breast cancer patients undergoing radiotherapy (RT). METHODS: Thirty women with breast cancer undergoing whole breast RT were enrolled. Each patient was randomly assigned to HA formulation (study cream, S) on the medial or lateral half of the irradiated breast and the control cream (placebo, P) on the other half. The primary endpoint was physician's evaluation of skin symptoms at week 5 during RT and week 2 post-RT. We also collected patients' independent assessment of skin after RT, patient's product preference, and an independent physician panel assessment of skin reactions based on photographs. RESULTS: Twenty-eight patients were evaluable. On physician's evaluation, there was no significant difference in radiation dermatitis between S and P and no overall preference to either cream at week 5 during or week 2 post-RT. More patients preferred S in evaluating skin appearance and skin reactions, but this did not reach statistical significance. Univariate analysis showed that physicians had an overall preference to the S cream at week 2 post-RT in patients with larger breasts. On the independent panel assessment, 3 reviewers saw no significant difference in radiation toxicity, whereas one reviewer reported better skin outcome with S cream at week 5. CONCLUSIONS: We found a nonstatistically significant patient preference but overall no significant radioprotective effects for this HA formulation compared with placebo except in patients with larger breasts. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02165605).
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Neoplasias de la Mama/radioterapia , Mama/anomalías , Ácido Hialurónico/uso terapéutico , Hipertrofia/prevención & control , Traumatismos por Radiación/prevención & control , Radiodermatitis/prevención & control , Adulto , Anciano , Mama/efectos de los fármacos , Mama/efectos de la radiación , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Pomadas , Radiodermatitis/tratamiento farmacológico , Piel/patología , Piel/efectos de la radiaciónRESUMEN
The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.
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Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Coriomeningitis Linfocítica/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Separación Celular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoglobulina G/inmunología , Virus de la Coriomeningitis Linfocítica , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
A Nd3+ fiber amplifier with gain from 1376 nm to 1466 nm is demonstrated. This is enabled by a wavelength selective waveguide that suppresses amplified spontaneous emission between 850 nm and 1150 nm. It is shown that while excited state absorption (ESA) precludes net gain below 1375 nm with the exception of a small band from 1333 nm to 1350 nm, ESA diminishes steadily beyond 1375 nm allowing for the construction of an efficient fiber amplifier with a gain peak at 1400 nm and the potential for gain from 1375 nm to 1500 nm. A peak small signal gain of 13.3 dB is measured at 1402 nm with a noise figure of 7.6 dB. Detailed measurements of the Nd3+ emission and excited state absorption cross sections suggest the potential for better performance in improved fibers. Specifically, reduction of the fiber mode field diameter from 10.5 µm to 5.25 µm and reduction of the fiber background loss to <10 dB/km at 1400 nm should enable construction of an E-band fiber amplifier with a noise figure < 5 dB and a small signal gain > 20 dB over 30 nm of bandwidth. Such an amplifier would have a form factor and optical properties similar to current erbium fiber amplifiers, enabling modern fiber optic communication systems to operate in the E-band with amplifier technology similar to that employed in the C and L bands.
RESUMEN
Approximately 10%-20% of germline pathogenic variants alter mRNA splicing, with phenotypes often dependent on the stability of the mRNA produced by the mutant allele. To better understand the relationships between genotype, mRNA splicing, and phenotype, we examined clinical and molecular data from 243 probands with osteogenesis imperfecta (OI) representing 145 unique splicing variants within the type I procollagen gene, COL1A1. All individuals with IVSX-1G>A mutations had OI type I because the substitution shifted the splice acceptor site 1 nt downstream and destabilized the mRNA. OI phenotypes were not consistent for any other splice variant identified. We sequenced all cDNA species from cultured dermal fibroblasts from 40 individuals to identify splice outcome and compared those results to splice predictions from Human Splice Finder (HSF), Spliceport (SP), and Automatic Splice Site and Exon Definition Analyses (ASSEDA). Software-based splice predictions were correct in 42%, 55%, and 74% instances for HSF, SP, and ASSEDA, respectively. As molecular diagnostics move increasingly to DNA sequence analysis, the need to understand the effects of splice site variants will increase. These data demonstrate that caution must be exercised when using splice prediction software to predict splice outcome.
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Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Empalme del ARN , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Cadena alfa 1 del Colágeno Tipo I , Simulación por Computador , Femenino , Fibroblastos/metabolismo , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Osteogénesis Imperfecta/genética , Fenotipo , Embarazo , Isoformas de Proteínas/metabolismo , Programas Informáticos , Adulto JovenRESUMEN
Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus-host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.
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Hepacivirus/inmunología , Hepatitis C/prevención & control , Vacunas Virales/uso terapéutico , Animales , Modelos Animales de Enfermedad , Epidemias , Hepatitis C/epidemiología , Humanos , Resultado del Tratamiento , Vacunas Virales/inmunologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Femenino , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Recurrencia Local de Neoplasia , Supervivencia sin ProgresiónRESUMEN
The impact of HIV-1 Nef-mediated HLA-I down-regulation on CD8(+) cytotoxic T lymphocytes (CTLs) varies by epitope, but the determining factors have not been elucidated. In the present study, we investigated the impact of Nef on the antiviral efficiency of HIV-1-specific CTLs targeting 17 different epitopes to define properties that determine susceptibility to Nef. The impact of Nef was not correlated with the presenting HLA-I type or functional avidity of CTLs, but instead was related directly to the kinetics of infected cell clearance. Whereas Gag-specific CTLs generally were less susceptible to Nef than those targeting other proteins, this was determined by the ability to eliminate infected cells before de novo synthesis of viral proteins, which was also observed for CTLs targeting a Nef epitope. This very early clearance of infected cells depended on virus inoculum, and the required inoculum varied by epitope. These results suggest that whereas Gag-specific CTLs are more likely to recognize infected cells before Nef-mediated HLA-I down-regulation, this varies depending on the specific epitope and virus inoculum. Reduced susceptibility to Nef therefore may contribute to the overall association of Gag-specific CTL responses to better immune control if a sufficient multiplicity of infection is attained in vivo, but this property is not unique to Gag.
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Epítopos de Linfocito T/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Linfocitos T Citotóxicos/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/inmunología , Presentación de Antígeno/inmunología , Células Cultivadas , Regulación hacia Abajo/inmunología , Regulación Viral de la Expresión Génica/fisiología , VIH-1/genética , VIH-1/crecimiento & desarrollo , Humanos , Linfocitos T Citotóxicos/citología , Transcripción Genética/fisiología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
BACKGROUND: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. OBJECTIVE: We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. METHODS: This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. RESULTS: A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. LIMITATIONS: Abbreviated follow-up time because of study termination upon FDA approval was a limitation. CONCLUSION: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Óseas/secundario , Carcinoma Basocelular/tratamiento farmacológico , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alopecia/inducido químicamente , Anilidas/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma Basocelular/secundario , Diarrea/inducido químicamente , Progresión de la Enfermedad , Disgeusia/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Neoplasias Cutáneas/patología , Espasmo/inducido químicamente , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. RESULTS: Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. CONCLUSIONS: ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. CLINICAL TRIAL REGISTRATION: NCT04272203.
Asunto(s)
Anticuerpos Biespecíficos , Complejo CD3 , Carcinoma de Pulmón de Células no Pequeñas , Relación Dosis-Respuesta a Droga , Leucemia Mieloide Aguda , Neoplasias Pulmonares , Receptores de Antígenos de Linfocitos T , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Persona de Mediana Edad , Masculino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/farmacología , Anciano , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Adulto , Antígeno HLA-A2RESUMEN
Background & Aims: Novel finite therapies for chronic hepatitis B (CHB) are needed, since lifelong treatment is usually required with current available oral antivirals. This phase II study (NCT03615066) evaluated the safety, pharmacodynamics, and antiviral activity of selgantolimod (a Toll-like receptor 8 agonist [TLR8]) with tenofovir alafenamide (TAF). Methods: Viremic patients with CHB not receiving treatment were stratified by HBeAg status and randomized 2:2:1 to TAF 25 mg/day with selgantolimod 3 mg orally once weekly (QW), selgantolimod 1.5 mg QW, or placebo. Combination therapy continued until week (W)24, followed by TAF monotherapy until W48; patients then discontinued TAF and were followed until W96 (treatment-free follow-up [TFFU] period). The primary efficacy endpoint was the proportion with ≥1 log10 IU/ml HBsAg decline at W24. Results: Sixty-seven patients received study drug; 27 were followed during TFFU. Nausea, headache, vomiting, fatigue, and dizziness were the most common adverse events. Most adverse events were grade 1. Alanine aminotransferase flares were not observed up to W48. Four patients experienced alanine aminotransferase and hepatitis flares during TFFU; all had HBV DNA increases. Selgantolimod increased serum cytokines and chemokines and redistributed several circulating immune cell subsets. No patients achieved the primary efficacy endpoint. Mean HBsAg changes were -0.12, -0.16, and -0.12 log10 IU/ml in the selgantolimod 3 mg, selgantolimod 1.5 mg, and placebo groups, respectively, at W48; HBV DNA declined in all groups by ≥2 log10 IU/ml as early as W2, with all groups rebounding to baseline during TFFU. No HBsAg or HBeAg loss or seroconversion was observed throughout TFFU. Conclusions: Selgantolimod up to 3 mg was safe and well tolerated. Pharmacodynamics and antiviral activity in viremic patients support continued study of selgantolimod in combination CHB therapies. Impact and implications: Novel therapeutics for chronic HBV infection are needed to achieve a functional cure. In this study, we confirmed the safety and tolerability of selgantolimod (formerly GS-9688, a TLR8) when administered with tenofovir alafenamide over 24 weeks in viremic patients with chronic HBV infection. Overall, declines in HBsAg levels with selgantolimod treatment were modest; subgroup analysis indicated that patients with alanine aminotransferase levels greater than the upper limit of normal had significantly greater declines compared to those with normal alanine aminotransferase levels (-0.20 vs. -0.03 log10 IU/ml; p <0.001). These findings suggest a potential differential response to selgantolimod based on patients' baseline HBV-specific immune response, which should be considered in future investigations characterizing the underlying mechanisms of selgantolimod treatment and in HBV cure studies using similar immunomodulatory pathways. Clinical trial number: NCT03615066 be found at https://www.gileadclinicaltrials.com/transparency-policy/.
RESUMEN
The hardest anatomical components of many animals are connected at thin seams known as sutures, which allow for growth and compliance required for respiration and movement and serve as a defense mechanism by absorbing energy during impacts. We take a bio-inspired approach and parameterize suture geometries to utilize geometric connections, rather than new engineering materials, to absorb high-impact loads. This study builds upon our work that investigated the effects of the dovetail suture contact angle, tangent length, and tab radius on the stiffness and toughness of an archway structure using finite element analysis. We explore how increasing the archway segmentation affects the mechanical response of the overall structure and investigate the effects of displacement when induced between sutures. First, when keeping displacement along a suture but increasing the number of archway pieces from two to four, we observed that stiffness and toughness were reduced substantially, although the overall trends stayed the same. Second, when the displacement was induced along an archway edge rather than upon a suture (in a three-piece archway), we observed that archway stiffness and toughness were much less sensitive to the changes in the suture parameters, but unlike the archway indented along the suture line, they tended to lose stiffness and toughness as the tangent length increased. This study is a step forward in the development of bio-inspired impact-resistant helmets.