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1.
Cancer Discov ; 12(9): 2023-2025, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36052501

RESUMO

SUMMARY: Autophagy is an adaptive response to metabolic and therapeutic stress, especially in treatment-refractory cancers such as pancreatic cancer. In this issue of Cancer Discovery, two groups establish ferritinophagy, a selective autophagy program that could become a drug target, as the mechanism that pumps iron into mitochondria via the lysosome, enabling survival and therapy resistance in pancreas cancer. See related article by Santana-Codina et al., p. 2180 (3). See related article by Ravichandran et al., p. 2198 (4).


Assuntos
Proteínas Ferro-Enxofre , Neoplasias Pancreáticas , Autofagia , Disponibilidade Biológica , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Coativadores de Receptor Nuclear/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Enxofre/metabolismo
2.
Nat Commun ; 13(1): 4078, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35835783

RESUMO

The lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8+ T cells into tumors. In tissue samples from patients with melanoma, CD8+ T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1+ immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.


Assuntos
Exossomos , Melanoma , Animais , Antígeno B7-H1 , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Exossomos/metabolismo , Humanos , Imunoterapia , Camundongos , Fosforilação , Receptor de Morte Celular Programada 1 , Microambiente Tumoral
3.
Oncologist ; 27(9): 799-808, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35666292

RESUMO

BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.


Assuntos
Colite , Melanoma , Colite/induzido quimicamente , Colite/complicações , Colite/tratamento farmacológico , Humanos , Ipilimumab/efeitos adversos , Melanoma/terapia , Estudos Retrospectivos , Esteroides/uso terapêutico
4.
Oncologist ; 27(9): 716-e689, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-35552447

RESUMO

BACKGROUND: The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response. METHODS: This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy. RESULTS: Twenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed. CONCLUSION: The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC. CLINICALTRIALS.GOV IDENTIFIER: NCT03215264.


Assuntos
Neoplasias Colorretais , Hidroxicloroquina , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Hidroxicloroquina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Piridinas , Redução de Peso
5.
Immunity ; 55(3): 557-574.e7, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263570

RESUMO

The clinical benefit of T cell immunotherapies remains limited by incomplete understanding of T cell differentiation and dysfunction. We generated an epigenetic and transcriptional atlas of T cell differentiation from healthy humans that included exhausted CD8 T cells and applied this resource in three ways. First, we identified modules of gene expression and chromatin accessibility, revealing molecular coordination of differentiation after activation and between central memory and effector memory. Second, we applied this healthy molecular framework to three settings-a neoadjuvant anti-PD1 melanoma trial, a basal cell carcinoma scATAC-seq dataset, and autoimmune disease-associated SNPs-yielding insights into disease-specific biology. Third, we predicted genome-wide cis-regulatory elements and validated this approach for key effector genes using CRISPR interference, providing functional annotation and demonstrating the ability to identify targets for non-coding cellular engineering. These studies define epigenetic and transcriptional regulation of human T cells and illustrate the utility of interrogating disease in the context of a healthy T cell atlas.


Assuntos
Epigenômica , Ativação Linfocitária , Linfócitos T CD8-Positivos , Diferenciação Celular/genética , Cromatina/genética , Cromatina/metabolismo , Epigênese Genética , Humanos , Ativação Linfocitária/genética
6.
Autophagy ; 18(6): 1470-1471, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35156519

RESUMO

Macroautophagy/autophagy is a resistance mechanism to targeted therapy in BRAF mutant cancers. Preclinical evidence and clinical trial data demonstrate that hydroxychloroquine (HCQ) is an effective autophagy inhibitor at clinically achievable concentrations. Here we highlight the results of a recently published single-arm phase I/II multi-institution trial of dabrafenib, trametinib, and the autophagy inhibitor HCQ (the BAMM trial) that established the safety and activity of this regimen in BRAF V600-mutant melanoma patients. Compared to the pivotal trials that led to FDA approval of dabrafenib and trametinib, the BAMM trial enrolled a high percentage of patients with elevated LDH and prior immunotherapy, reflecting the trend that poorer-prognosis patients are treated with targeted therapy in the modern era where multiple immunotherapy regimens are available for melanoma. Dabrafenib, trametinib, and hydroxychloroquine are safe and produce a high response rate (85%). Progression-free survival does not meet the pre-specified threshold for the entire cohort but looks especially promising in patients with elevated LDH and prior treatment. A national randomized study has been launched to study this regimen further in poor-prognosis BRAF V600-mutant melanoma patients.


Assuntos
Melanoma , Neoplasias Cutâneas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autofagia/genética , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico
7.
Clin Cancer Res ; 28(6): 1098-1106, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35022320

RESUMO

PURPOSE: Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T). PATIENTS AND METHODS: We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%. RESULTS: Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively. CONCLUSIONS: HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autofagia , Humanos , Hidroxicloroquina/uso terapêutico , Imidazóis , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico
8.
Int J Mol Sci ; 22(22)2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34830283

RESUMO

RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.


Assuntos
Autofagia/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas ras/antagonistas & inibidores , Proteínas ras/genética , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada/métodos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Resultado do Tratamento , Proteínas ras/metabolismo
9.
EMBO J ; 40(19): e108863, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34459017

RESUMO

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.


Assuntos
Autofagia , Suscetibilidade a Doenças , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Autofagia/imunologia , Biomarcadores , Regulação da Expressão Gênica , Predisposição Genética para Doença , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Especificidade de Órgãos , Transdução de Sinais
10.
Cancer Res ; 81(20): 5230-5241, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34462276

RESUMO

Metastatic melanoma is challenging to clinically address. Although standard-of-care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSC) including high invasiveness, plasticity, and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi ± MEKi efficacy and ablated melanoma migration and invasion. Our data define LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells. SIGNIFICANCE: This study identifies an LPAR1-axis critical for melanoma invasion and intrinsic/acquired therapy resistance.


Assuntos
Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Melanoma/patologia , Crista Neural/patologia , Células-Tronco Neurais/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Crista Neural/efeitos dos fármacos , Crista Neural/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Prognóstico , Receptores de Ácidos Lisofosfatídicos/genética , Transcriptoma , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer ; 127(19): 3591-3598, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34292585

RESUMO

BACKGROUND: Sentinel lymph node biopsy (SLNB) has not been studied for invasive melanomas treated with Mohs micrographic surgery using frozen-section MART-1 immunohistochemical stains (MMS-IHC). The primary objective of this study was to assess the accuracy and compliance with National Comprehensive Cancer Network (NCCN) guidelines for SLNB in a cohort of patients who had invasive melanoma treated with MMS-IHC. METHODS: This retrospective cohort study included all patients who had primary, invasive, cutaneous melanomas treated with MMS-IHC at a single academic center between March 2006 and April 2018. The primary outcomes were the rates of documenting discussion and performing SLNB in patients who were eligible based on NCCN guidelines. Secondary outcomes were the rate of identifying the sentinel lymph node and the percentage of positive lymph nodes. RESULTS: In total, 667 primary, invasive, cutaneous melanomas (American Joint Committee on Cancer T1a-T4b) were treated with MMS-IHC. The median patient age was 69 years (range, 25-101 years). Ninety-two percent of tumors were located on specialty sites (head and/or neck, hands and/or feet, pretibial leg). Discussion of SLNB was documented for 162 of 176 (92%) SLNB-eligible patients, including 127 of 127 (100%) who had melanomas with a Breslow depth >1 mm. SLNB was performed in 109 of 176 (62%) SLNB-eligible patients, including 102 of 158 melanomas (65%) that met NCCN criteria to discuss and offer SLNB and 7 of 18 melanomas (39%) that met criteria to discuss and consider SLNB. The sentinel lymph node was successfully identified in 98 of 109 patients (90%) and was positive in 6 of those 98 patients (6%). CONCLUSIONS: Combining SLNB and MMS-IHC allows full pathologic staging and confirmation of clear microscopic margins before reconstruction of specialty site invasive melanomas. SLNB can be performed accurately and in compliance with consensus guidelines in patients with melanoma using MMS-IHC.


Assuntos
Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Cirurgia de Mohs , Estudos Retrospectivos , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia
12.
Bioorg Med Chem Lett ; 49: 128272, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34298133

RESUMO

We have previously reported the unique features of dimeric bisaminoquinolines as anticancer agents and have identified their cellular target as PPT1, a protein palmitoyl-thioesterase. We now report a systematic study on the role of the linker in these constructs, both with respect to the distance between the heterocycles, the linker hydrophobicity and the methylation status (primary vs. secondary vs. tertiary) of the central nitrogen atom on the observed biological activity.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Aminoquinolinas/síntese química , Antineoplásicos/síntese química , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas de Membrana/antagonistas & inibidores , Estrutura Molecular , Tioléster Hidrolases/antagonistas & inibidores
14.
Cell Rep ; 35(6): 109120, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979613

RESUMO

The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of T-bet and Eomes dictate their regulatory activity in exhausted T cells (TEXs). TEXs had a higher ratio of nuclear Eomes:T-bet than memory T cells (TMEMs) during chronic lymphocytic choriomeningitis virus (LCMV) infection in preclinical cancer models and in human tumors. Biochemically, T-bet and Eomes compete for the same DNA sequences, including the Pdcd1 T-box. High nuclear T-bet strongly represses Pdcd1 transcription in TMEM, whereas low nuclear T-bet in TEX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in TEXs increases nuclear T-bet, restoring stronger repression of Pdcd1, and driving T-bet-associated gene expression programs of chemotaxis, homing, and activation. These data identify a mechanism whereby the T-bet-Eomes axis regulates exhaustion through their nuclear localization, providing insights into how these transcription factors regulate TEX biology.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Proteínas com Domínio T/metabolismo , Animais , Diferenciação Celular , Humanos , Camundongos , Transdução de Sinais
15.
Nat Commun ; 12(1): 2349, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859192

RESUMO

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/mortalidade , Cloroquina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Complicações Infecciosas na Gravidez/mortalidade , Adulto , COVID-19/complicações , COVID-19/virologia , Criança , Cloroquina/administração & dosagem , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Comorbidade , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Cooperação Internacional , Razão de Chances , Participação do Paciente/estatística & dados numéricos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , SARS-CoV-2
16.
Oncoimmunology ; 10(1): 1863631, 2021 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-33643689

RESUMO

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).


Assuntos
Melanoma , Segunda Neoplasia Primária , Seguimentos , Humanos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Intervalo Livre de Progressão
17.
Br J Clin Pharmacol ; 87(3): 1291-1302, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32736411

RESUMO

AIMS: We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). METHODS: This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75-mg dose on Day 1 of run-in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28-day cycle after the run-in period in both cohorts. RESULTS: The geometric means ratios [90% confidence interval] for (S)-warfarin with and without sonidegib were: area under the concentration-time curve from time 0 to infinity (AUCinf ) 1.15 [1.07, 1.24] and maximum plasma concentration (Cmax ) 0.88 [0.81, 0.97]; and for (R)-warfarin were: AUCinf 1.10 [0.98, 1.24] and Cmax 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUCinf 1.10 [0.99, 1.23] and Cmax 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. CONCLUSIONS: Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration-approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).


Assuntos
Neoplasias , Varfarina , Administração Oral , Área Sob a Curva , Compostos de Bifenilo , Bupropiona/uso terapêutico , Interações Medicamentosas , Humanos , Neoplasias/tratamento farmacológico , Piridinas
18.
J Natl Cancer Inst ; 113(2): 162-170, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32294209

RESUMO

BACKGROUND: Gut microbial diversity is associated with improved response to immune checkpoint inhibitors (ICI). Based on the known detrimental impact that antibiotics have on microbiome diversity, we hypothesized that antibiotic receipt prior to ICI would be associated with decreased survival. METHODS: Patients with stage III and IV melanoma treated with ICI between 2008 and 2019 were selected from an institutional database. A window of antibiotic receipt within 3 months prior to the first infusion of ICI was prespecified. The primary outcome was overall survival (OS), and secondary outcomes were melanoma-specific mortality and immune-mediated colitis requiring intravenous steroids. All statistical tests were two-sided. RESULTS: There were 568 patients in our database of which 114 received antibiotics prior to ICI. Of the patients, 35.9% had stage III disease. On multivariable Cox proportional hazards analysis of patients with stage IV disease, the antibiotic-exposed group had statistically significantly worse OS (hazard ratio [HR] = 1.81, 95% confidence interval [CI] = 1.27 to 2.57; P <.001). The same effect was observed among antibiotic-exposed patients with stage III disease (HR = 2.78, 95% CI = 1.31 to 5.87; P =.007). When limited to only patients who received adjuvant ICI (n = 89), antibiotic-exposed patients also had statistically significantly worse OS (HR = 4.84, 95% CI = 1.09 to 21.50; P =.04). The antibiotic group had a greater incidence of colitis (HR = 2.14, 95% CI = 1.02 to 4.52; P =.046). CONCLUSION: Patients with stage III and IV melanoma exposed to antibiotics prior to ICI had statistically significantly worse OS than unexposed patients. Antibiotic exposure was associated with greater incidence of moderate to severe immune-mediated colitis. Given the large number of antibiotics prescribed annually, physicians should be judicious with their use in cancer populations likely to receive ICI.


Assuntos
Antibacterianos/efeitos adversos , Microbioma Gastrointestinal/genética , Variação Genética/efeitos dos fármacos , Melanoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Variação Genética/genética , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/efeitos adversos , Fatores Imunológicos/antagonistas & inibidores , Fatores Imunológicos/genética , Imunoterapia/efeitos adversos , Masculino , Melanoma/microbiologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto Jovem
19.
JAMA Intern Med ; 181(2): 195-202, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001138

RESUMO

Importance: Health care workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) are at risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, to our knowledge, there is no effective pharmacologic prophylaxis for individuals at risk. Objective: To evaluate the efficacy of hydroxychloroquine to prevent transmission of SARS-CoV-2 in hospital-based HCWs with exposure to patients with COVID-19 using a pre-exposure prophylaxis strategy. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled clinical trial (the Prevention and Treatment of COVID-19 With Hydroxychloroquine Study) was conducted at 2 tertiary urban hospitals, with enrollment from April 9, 2020, to July 14, 2020; follow-up ended August 4, 2020. The trial randomized 132 full-time, hospital-based HCWs (physicians, nurses, certified nursing assistants, emergency technicians, and respiratory therapists), of whom 125 were initially asymptomatic and had negative results for SARS-CoV-2 by nasopharyngeal swab. The trial was terminated early for futility before reaching a planned enrollment of 200 participants. Interventions: Hydroxychloroquine, 600 mg, daily, or size-matched placebo taken orally for 8 weeks. Main Outcomes and Measures: The primary outcome was the incidence of SARS-CoV-2 infection as determined by a nasopharyngeal swab during the 8 weeks of treatment. Secondary outcomes included adverse effects, treatment discontinuation, presence of SARS-CoV-2 antibodies, frequency of QTc prolongation, and clinical outcomes for SARS-CoV-2-positive participants. Results: Of the 132 randomized participants (median age, 33 years [range, 20-66 years]; 91 women [69%]), 125 (94.7%) were evaluable for the primary outcome. There was no significant difference in infection rates in participants randomized to receive hydroxychloroquine compared with placebo (4 of 64 [6.3%] vs 4 of 61 [6.6%]; P > .99). Mild adverse events were more common in participants taking hydroxychloroquine compared with placebo (45% vs 26%; P = .04); rates of treatment discontinuation were similar in both arms (19% vs 16%; P = .81). The median change in QTc (baseline to 4-week evaluation) did not differ between arms (hydroxychloroquine: 4 milliseconds; 95% CI, -9 to 17; vs placebo: 3 milliseconds; 95% CI, -5 to 11; P = .98). Of the 8 participants with positive results for SARS-CoV-2 (6.4%), 6 developed viral symptoms; none required hospitalization, and all clinically recovered. Conclusions and Relevance: In this randomized clinical trial, although limited by early termination, there was no clinical benefit of hydroxychloroquine administered daily for 8 weeks as pre-exposure prophylaxis in hospital-based HCWs exposed to patients with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04329923.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Infecção Hospitalar/prevenção & controle , Infecção Hospitalar/virologia , Hidroxicloroquina/administração & dosagem , Recursos Humanos em Hospital , Profilaxia Pré-Exposição , Adulto , COVID-19/epidemiologia , Método Duplo-Cego , Feminino , Hospitais Urbanos , Humanos , Incidência , Masculino , Pennsylvania/epidemiologia , SARS-CoV-2
20.
Cell Rep ; 33(13): 108571, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378668

RESUMO

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Calgranulina A/fisiologia , Calgranulina B/fisiologia , Macrófagos/metabolismo , Monócitos/metabolismo , Células Supressoras Mieloides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Pessoa de Meia-Idade , Células Supressoras Mieloides/imunologia , Microambiente Tumoral
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