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[PMID]:29444087
[Au] Autor:Balsitis S; Gali V; Mason PJ; Chaniewski S; Levine SM; Wichroski MJ; Feulner M; Song Y; Granaldi K; Loy JK; Thompson CM; Lesniak JA; Brockus C; Kishnani N; Menne S; Cockett MI; Iyer R; Mason SW; Tenney DJ
[Ad] Endereço:Virology Discovery, Bristol-Myers Squibb, Wallingford, Connecticut, United States of America.
[Ti] Título:Safety and efficacy of anti-PD-L1 therapy in the woodchuck model of HBV infection.
[So] Source:PLoS One;13(2):e0190058, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Immune clearance of Hepatitis B virus (HBV) is characterized by broad and robust antiviral T cell responses, while virus-specific T cells in chronic hepatitis B (CHB) are rare and exhibit immune exhaustion that includes programmed-death-1 (PD-1) expression on virus-specific T cells. Thus, an immunotherapy able to expand and activate virus-specific T cells may have therapeutic benefit for CHB patients. Like HBV-infected patients, woodchucks infected with woodchuck hepatitis virus (WHV) can have increased hepatic expression of PD-1-ligand-1 (PD-L1), increased PD-1 on CD8+ T cells, and a limited number of virus-specific T cells with substantial individual variation in these parameters. We used woodchucks infected with WHV to assess the safety and efficacy of anti-PD-L1 monoclonal antibody therapy (αPD-L1) in a variety of WHV infection states. Experimentally-infected animals lacked PD-1 or PD-L1 upregulation compared to uninfected controls, and accordingly, αPD-L1 treatment in lab-infected animals had limited antiviral effects. In contrast, animals with naturally acquired WHV infections displayed elevated PD-1 and PD-L1. In these same animals, combination therapy with αPD-L1 and entecavir (ETV) improved control of viremia and antigenemia compared to ETV treatment alone, but with efficacy restricted to a minority of animals. Pre-treatment WHV surface antigen (sAg) level was identified as a statistically significant predictor of treatment response, while PD-1 expression on peripheral CD8+ T cells, T cell production of interferon gamma (IFN-γ) upon in vitro antigen stimulation (WHV ELISPOT), and circulating levels of liver enzymes were not. To further assess the safety of this strategy, αPD-L1 was tested in acute WHV infection to model the risk of liver damage when the extent of hepatic infection and antiviral immune responses were expected to be the greatest. No significant increase in serum markers of hepatic injury was observed over those in infected, untreated control animals. These data support a positive benefit/risk assessment for blockade of the PD-1:PD-L1 pathway in CHB patients and may help to identify patient groups most likely to benefit from treatment. Furthermore, the efficacy of αPD-L1 in only a minority of animals, as observed here, suggests that additional agents may be needed to achieve a more robust and consistent response leading to full sAg loss and durable responses through anti-sAg antibody seroconversion.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Antígeno B7-H1/imunologia
Modelos Animais de Doenças
Hepatite B/terapia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/efeitos adversos
Marmota
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (B7-H1 Antigen); 0 (CD274 protein, human)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190058


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[PMID]:29322203
[Au] Autor:Dada R
[Ad] Endereço:Department of Oncology MBC J-64, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah, 21499, Kingdom of Saudi Arabia. rdada@kfshrc.edu.sa.
[Ti] Título:Program death inhibitors in classical Hodgkin's lymphoma: a comprehensive review.
[So] Source:Ann Hematol;97(4):555-561, 2018 Apr.
[Is] ISSN:1432-0584
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Cancer cells are able to induce immune system tolerance through different mechanisms. Recent achievements in the understanding of tumor microenvironment, invasion, and metastasizing have contributed to accelerated drug developments and approvals. Hodgkin lymphoma (HL) cells are the minority in a lymphocyte-rich microenvironment of HL tissue. The program death-1 (PD-1)/PD-ligand-1 checkpoint is one of the known effective pathways in classical HL to escape the immune system cells. The approval of PD-1 inhibitors in different cancer types with exciting response rates is truly revolutionizing our treatment armamentarium against cancer in general and classical HL in specific. Although the disease is one of the most curable tumors, we still need better outcome with more gentle treatment, especially for relapsed and refractory (r/r) patients. In this article, we review the current literature on immune checkpoint inhibitors and currently ongoing studies with nivolumab and pembrolizumab in r/r classical HL.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Antígeno B7-H1/antagonistas & inibidores
Doença de Hodgkin/tratamento farmacológico
Proteínas de Neoplasias/antagonistas & inibidores
Receptor de Morte Celular Programada 1/antagonistas & inibidores
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/efeitos adversos
Anticorpos Monoclonais/uso terapêutico
Anticorpos Monoclonais Humanizados/efeitos adversos
Anticorpos Monoclonais Humanizados/uso terapêutico
Antineoplásicos/efeitos adversos
Antineoplásicos Imunológicos/efeitos adversos
Antineoplásicos Imunológicos/uso terapêutico
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Antígeno B7-H1/metabolismo
Aprovação de Drogas
Resistência a Múltiplos Medicamentos
Resistência a Medicamentos Antineoplásicos
Doença de Hodgkin/metabolismo
Seres Humanos
Terapia de Alvo Molecular/efeitos adversos
Proteínas de Neoplasias/metabolismo
Receptor de Morte Celular Programada 1/metabolismo
Qualidade de Vida
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents); 0 (Antineoplastic Agents, Immunological); 0 (B7-H1 Antigen); 0 (CD274 protein, human); 0 (Neoplasm Proteins); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 31YO63LBSN (nivolumab); DPT0O3T46P (pembrolizumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1007/s00277-017-3226-0


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[PMID]:28922790
[Au] Autor:Marisa L; Svrcek M; Collura A; Becht E; Cervera P; Wanherdrick K; Buhard O; Goloudina A; Jonchère V; Selves J; Milano G; Guenot D; Cohen R; Colas C; Laurent-Puig P; Olschwang S; Lefèvre JH; Parc Y; Boige V; Lepage C; André T; Fléjou JF; Dérangère V; Ghiringhelli F; de Reynies A; Duval A
[Ad] Endereço:Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe "Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC U
[Ti] Título:The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Biomarcadores Tumorais/imunologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/imunologia
Linfócitos do Interstício Tumoral
Linfócitos T Citotóxicos
[Mh] Termos MeSH secundário: Antígenos CD/genética
Antígeno B7-H1/análise
Antígeno B7-H1/genética
Antígenos CD8/análise
Antígeno CTLA-4/genética
Colo/química
Neoplasias Colorretais/química
Neoplasias Colorretais/patologia
Feminino
Expressão Gênica
Receptor Celular 2 do Vírus da Hepatite A/genética
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Masculino
Instabilidade de Microssatélites
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Proteína 2 Ligante de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/genética
Estudos Retrospectivos
Taxa de Sobrevida
Células Th1
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antigens, CD); 0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD223 antigen); 0 (CD274 protein, human); 0 (CD8 Antigens); 0 (CTLA-4 Antigen); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (PDCD1LG2 protein, human); 0 (Programmed Cell Death 1 Ligand 2 Protein); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx136


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[PMID]:28460468
[Au] Autor:Jiang L; Su X; Zhang T; Yin X; Zhang M; Fu H; Han H; Sun Y; Dong L; Qian J; Xu Y; Fu X; Gavine PR; Zhou Y; Tian K; Huang J; Shen D; Jiang H; Yao Y; Han B; Gu Y
[Ad] Endereço:Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
[Ti] Título:PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC).
[So] Source:Oncotarget;8(16):26845-26857, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In order to explore the potential patient population who could benefit from anti PD-1/PD-L1 mono or combination therapies, this study aimed to profile a panel of immunotherapy related biomarkers (PD-1, PD-L1, CTLA-4 and CD8) and targeted therapy biomarkers (EGFR, KRAS, ALK, ROS1 and MET) in NSCLC.Tumor samples from 297 NSCLC patients, including 156 adenocarcinomas (AD) and 129 squamous cell carcinomas (SCC), were analyzed using immunohistochemistry, immunofluorescence, sequencing and fluorescence in situ hybridization.43.1% of NSCLC patients had PD-L1 positive staining on ≥ 5% tumor cells (TC). Furthermore, dual color immunofluorescence revealed that the majority of PD-L1/CD8 dual positive tumor infiltrating lymphocytes (TIL) had infiltrated into the tumor core. Finally, combined analysis of all eight biomarkers showed that tumor PD-L1 positivity overlapped with known alterations in NSCLC oncogenic tumor drivers in 26% of SCC and 76% of AD samples.Our illustration of the eight biomarkers' overlap provides an intuitive overview of NSCLC for personalized therapeutic strategies using anti-PD-1/PD-L1 immune therapies, either as single agents, or in combination with targeted therapies. For the first time, we also report that PD-L1 and CD8 dual positive TILs are predominantly located within the tumor core.
[Mh] Termos MeSH primário: Antígeno B7-H1/genética
Biomarcadores Tumorais
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/patologia
Expressão Gênica
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Antígeno B7-H1/metabolismo
Antígeno CTLA-4/genética
Antígeno CTLA-4/metabolismo
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Carcinoma Pulmonar de Células não Pequenas/cirurgia
Transformação Celular Neoplásica/genética
Feminino
Amplificação de Genes
Seres Humanos
Imuno-Histoquímica
Hibridização in Situ Fluorescente
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/cirurgia
Linfócitos do Interstício Tumoral/imunologia
Linfócitos do Interstício Tumoral/metabolismo
Masculino
Meia-Idade
Mutação
Gradação de Tumores
Estadiamento de Neoplasias
Receptor de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (CTLA-4 Antigen); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15839


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[PMID]:28460462
[Au] Autor:Ness N; Andersen S; Khanehkenari MR; Nordbakken CV; Valkov A; Paulsen EE; Nordby Y; Bremnes RM; Donnem T; Busund LT; Richardsen E
[Ad] Endereço:Department of Medical Biology, UiT The Arctic University of Norway, N-9037 Tromso, Norway.
[Ti] Título:The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort.
[So] Source:Oncotarget;8(16):26789-26801, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Programmed cell death protein 1 (PD-1) and its ligand Programmed death ligand 1 (PD-L1) have gained massive attention in cancer research due to recent availability and their targeted antitumor effects. Their role in prostate cancer is still undetermined. We constructed tissue microarrays from prostatectomy specimens from 535 prostate cancer patients. Following validation of antibodies, immunohistochemistry was used to evaluate the expression of PD-1 in lymphocytes and PD-L1 in epithelial and stromal cells of primary tumors. PD-L1 expression was commonly seen in tumor epithelial cells (92% of cases). Univariate survival analysis revealed a positive association between a high density of PD-1+ lymphocytes and worse clinical failure-free survival, limited to a trend (p = 0.084). In subgroups known to indicate unfavorable prostate cancer prognosis (Gleason grade 9, age < 65, preoperative PSA > 10, pT3) patients with high density of PD-1+ lymphocytes had a significantly higher risk of clinical failure (p = < 0.001, p = 0.025, p = 0.039 and p = 0.011, respectively). In the multivariate analysis, high density of PD-1+ lymphocytes was a significant negative independent prognostic factor for clinical failure-free survival (HR = 2.48, CI 95% 1.12-5.48, p = 0.025).
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Biomarcadores Tumorais
Imunomodulação
Receptor de Morte Celular Programada 1/metabolismo
Neoplasias da Próstata/imunologia
Neoplasias da Próstata/metabolismo
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Fibroblastos Associados a Câncer/metabolismo
Seres Humanos
Imuno-Histoquímica
Imunofenotipagem
Linfócitos do Interstício Tumoral/imunologia
Linfócitos do Interstício Tumoral/metabolismo
Masculino
Meia-Idade
Gradação de Tumores
Estadiamento de Neoplasias
Prognóstico
Neoplasias da Próstata/mortalidade
Neoplasias da Próstata/patologia
Reprodutibilidade dos Testes
Análise Serial de Tecidos
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15817


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[PMID]:28747424
[Au] Autor:Schwartz C; Khan AR; Floudas A; Saunders SP; Hams E; Rodewald HR; McKenzie ANJ; Fallon PG
[Ad] Endereço:Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, Dublin, Ireland.
[Ti] Título:ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control.
[So] Source:J Exp Med;214(9):2507-2521, 2017 Sep 04.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Group 2 innate lymphoid cells (ILC2s) are important effector cells driving the initiation of type 2 immune responses leading to adaptive T helper 2 (Th2) immunity. Here we show that ILC2s dynamically express the checkpoint inhibitor molecule PD-L1 during type 2 pulmonary responses. Surprisingly, PD-L1:PD-1 interaction between ILC2s and CD4 T cells did not inhibit the T cell response, but PD-L1-expressing ILC2s stimulated increased expression of GATA3 and production of IL-13 by Th2 cells both in vitro and in vivo. Conditional deletion of PD-L1 on ILC2s impaired early Th2 polarization and cytokine production, leading to delayed worm expulsion during infection with the gastrointestinal helminth Our results identify a novel PD-L1-controlled mechanism for type 2 polarization, with ILC2s mediating an innate checkpoint to control adaptive T helper responses, which has important implications for the treatment of type 2 inflammation.
[Mh] Termos MeSH primário: Antígeno B7-H1/fisiologia
Linfócitos/fisiologia
Células Th2/fisiologia
[Mh] Termos MeSH secundário: Imunidade Adaptativa/imunologia
Imunidade Adaptativa/fisiologia
Animais
Antígeno B7-H1/imunologia
Fator de Transcrição GATA3/fisiologia
Imunidade Celular/imunologia
Imunidade Celular/fisiologia
Interleucina-13/fisiologia
Linfócitos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Nippostrongylus/imunologia
Infecções por Strongylida/imunologia
Células Th2/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Cd274 protein, mouse); 0 (GATA3 Transcription Factor); 0 (Gata3 protein, mouse); 0 (Interleukin-13)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20170051


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[PMID]:29290331
[Au] Autor:Bernard-Tessier A; Bonnet C; Lavaud P; Gizzi M; Loriot Y; Massard C
[Ad] Endereço:University of Paris Sud, Gustave Roussy cancer campus, drug development department, 94805 Villejuif cedex, France; University of Paris Sud, Gustave Roussy cancer campus, department of medical oncology, 94805 Villejuif cedex, France.
[Ti] Título:[Atezolizumab (Tecentriq ): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].
[Ti] Título:Atézolizumab (Tecentriq ) : activité, indication et modalités d'utilisation dans les carcinomes urothéliaux localement avancés ou métastatiques..
[So] Source:Bull Cancer;105(2):140-145, 2018 Feb.
[Is] ISSN:1769-6917
[Cp] País de publicação:France
[La] Idioma:fre
[Ab] Resumo:Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq ) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Antineoplásicos/uso terapêutico
Carcinoma de Células de Transição/tratamento farmacológico
Neoplasias da Bexiga Urinária/tratamento farmacológico
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/administração & dosagem
Anticorpos Monoclonais/farmacocinética
Antineoplásicos/administração & dosagem
Antineoplásicos/efeitos adversos
Antineoplásicos/farmacocinética
Antígeno B7-H1/metabolismo
Carcinoma de Células de Transição/metabolismo
Carcinoma de Células de Transição/mortalidade
Carcinoma de Células de Transição/patologia
Cisplatino/efeitos adversos
Ensaios Clínicos Fase I como Assunto
Ensaios Clínicos Fase II como Assunto
Ensaios Clínicos Fase III como Assunto
Contraindicações de Medicamentos
Seres Humanos
Neoplasias da Bexiga Urinária/metabolismo
Neoplasias da Bexiga Urinária/mortalidade
Neoplasias da Bexiga Urinária/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (B7-H1 Antigen); 52CMI0WC3Y (atezolizumab); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180102
[St] Status:MEDLINE


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[PMID]:27776977
[Au] Autor:Singh P; Black P
[Ad] Endereço:Division of Hematology and Oncology , Mayo clinic, Phoenix, AZ. Electronic address: drparminder.singh@me.com.
[Ti] Título:Emerging role of checkpoint inhibition in localized bladder cancer.
[So] Source:Urol Oncol;34(12):548-555, 2016 12.
[Is] ISSN:1873-2496
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Checkpoint inhibitors have rapidly become a standard treatment option for metastatic urothelial carcinoma. A wave of enthusiasm for these drugs has pushed them also into the setting of localized bladder cancer, including both non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive disease bladder cancer (MIBC). Here, we aimed to review the emerging role of checkpoint inhibition in localized bladder cancer. METHODS: We reviewed the current treatment landscape for both NMIBC and MIBC and established a significant unmet clinical need for novel therapies. We have compiled the evidence that supports the investigation of checkpoint blockade in localized bladder cancer and have reviewed the corresponding clinical trial׳s landscape. RESULTS: The success of checkpoint inhibitors in metastatic bladder cancer offers the most compelling rationale for testing checkpoint blockade in localized disease. The established benefit of intravesical Bacillus Calmette-Guérin provides precedent for immune therapy in bladder cancer. Immune dysfunction has been described in bladder cancer, and we know that checkpoint molecules are expressed in these tumors. Furthermore, the high neoantigen burden of bladder cancer and results from preclinical studies suggest that checkpoint blockade deserves testing in earlier stage disease. Multiple trials are either planned or underway in almost all bladder cancer disease states. CONCLUSION: Ongoing trials would determine in the next several years whether checkpoint inhibitors can have a similar effect in localized disease as they have had in metastatic bladder cancer. They would also determine if patients with earlier disease would tolerate the toxicity of systemic therapy. The future holds promise for predictive biomarkers to guide individualized use of these agents and for effective combination therapies to overcome resistances.
[Mh] Termos MeSH primário: Antineoplásicos Imunológicos/uso terapêutico
Carcinoma de Células de Transição/terapia
Imunoterapia
Terapia de Alvo Molecular
Neoplasias da Bexiga Urinária/terapia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/uso terapêutico
Antineoplásicos Imunológicos/efeitos adversos
Antígeno B7-H1/antagonistas & inibidores
Antígeno B7-H1/imunologia
Antígeno CTLA-4/antagonistas & inibidores
Antígeno CTLA-4/imunologia
Carcinoma de Células de Transição/tratamento farmacológico
Carcinoma de Células de Transição/imunologia
Carcinoma de Células de Transição/cirurgia
Ensaios Clínicos como Assunto
Terapia Combinada
Cistectomia
Seres Humanos
Ipilimumab/uso terapêutico
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Receptor de Morte Celular Programada 1/imunologia
Radioterapia Adjuvante
Subpopulações de Linfócitos T/efeitos dos fármacos
Subpopulações de Linfócitos T/imunologia
Evasão Tumoral
Neoplasias da Bexiga Urinária/tratamento farmacológico
Neoplasias da Bexiga Urinária/imunologia
Neoplasias da Bexiga Urinária/cirurgia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents, Immunological); 0 (B7-H1 Antigen); 0 (CD274 protein, human); 0 (CTLA-4 Antigen); 0 (Ipilimumab); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 52CMI0WC3Y (atezolizumab)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


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[PMID]:27773553
[Au] Autor:Park JC; Hahn NM
[Ad] Endereço:Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University in Baltimore, Baltimore, MD.
[Ti] Título:Emerging role of immunotherapy in urothelial carcinoma-Future directions and novel therapies.
[So] Source:Urol Oncol;34(12):566-576, 2016 12.
[Is] ISSN:1873-2496
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tremendous advances in our understanding of the tumor immunology and molecular biology of urothelial carcinoma (UC) have led to the recent approval of immunotherapy as a novel option for patients with UC with advanced disease. Despite the promising data of novel immune checkpoint inhibitors, only a small subset of patients with UC achieves durable remissions. Because an optimal antitumor response requires coordination of multiple immune, tumor, and microenvironment effector cells, novel approaches targeting distinct mechanisms of action likely in combination are needed. In addition, discovery of reliable immune biomarkers, understanding of mechanisms of resistance, and novel clinical trial designs are warranted for maximum benefit of UC immunotherapy.
[Mh] Termos MeSH primário: Antineoplásicos Imunológicos/uso terapêutico
Carcinoma de Células de Transição/terapia
Imunoterapia
Terapia de Alvo Molecular
Terapias em Estudo
Neoplasias da Bexiga Urinária/terapia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/efeitos adversos
Anticorpos Monoclonais/uso terapêutico
Antineoplásicos Imunológicos/efeitos adversos
Antígeno B7-H1/antagonistas & inibidores
Antígeno B7-H1/imunologia
Biomarcadores Tumorais
Carcinoma de Células de Transição/tratamento farmacológico
Carcinoma de Células de Transição/imunologia
Ensaios Clínicos como Assunto
Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores
Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia
Previsões
Seres Humanos
Imunidade Inata
Imunoterapia Adotiva
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/imunologia
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Receptor de Morte Celular Programada 1/imunologia
Projetos de Pesquisa
Evasão Tumoral/efeitos dos fármacos
Evasão Tumoral/imunologia
Microambiente Tumoral/imunologia
Neoplasias da Bexiga Urinária/tratamento farmacológico
Neoplasias da Bexiga Urinária/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents, Immunological); 0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (Costimulatory and Inhibitory T-Cell Receptors); 0 (Neoplasm Proteins); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 31YO63LBSN (nivolumab); 52CMI0WC3Y (atezolizumab)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:28451792
[Au] Autor:Chen N; Fang W; Lin Z; Peng P; Wang J; Zhan J; Hong S; Huang J; Liu L; Sheng J; Zhou T; Chen Y; Zhang H; Zhang L
[Ad] Endereço:State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, People's Republic of China.
[Ti] Título:KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma.
[So] Source:Cancer Immunol Immunother;66(9):1175-1187, 2017 Sep.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Antígeno B7-H1/metabolismo
Neoplasias Pulmonares/genética
Proteínas Proto-Oncogênicas p21(ras)/genética
Evasão Tumoral
[Mh] Termos MeSH secundário: Adenocarcinoma/patologia
Antígeno B7-H1/genética
Linhagem Celular Tumoral
Seres Humanos
Neoplasias Pulmonares/patologia
Meia-Idade
Mutação
Estudos Prospectivos
Transdução de Sinais
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (CD274 protein, human); 0 (KRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-017-2005-z



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