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https://www.readbyqxmd.com/read/27903604/what-does-pd-l1-positive-or-negative-mean
#1
Antoni Ribas, Siwen Hu-Lieskovan
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti-PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response...
November 30, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27903500/primary-resistance-to-pd-1-blockade-mediated-by-jak%C3%A2-mutations
#2
Daniel Sanghoon Shin, Jesse M Zaretsky, Helena Escuin-Ordinas, Angel Garcia-Diaz, Siwen Hu-Lieskovan, Anusha Kalbasi, Catherine S Grasso, Willy Hugo, Salemiz Sandoval, Davis Y Torrejon, Nicolaos Palaskas, Gabriel Abril Rodriguez, Giulia Parisi, Ariel Azhdam, Bartosz Chmielowski, Grace Cherry, Elizabeth Seja, Beata Berent-Maoz, I Peter Shintaku, Dung Thi Le, Drew M Pardoll, Luis A Diaz, Paul C Tumeh, Thomas G Graeber, Roger S Lo, Begoña Comin-Anduix, Antoni Ribas
Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway...
November 30, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27864013/factors-predictive-of-response-disease-progression-and-overall-survival-after-dabrafenib-and-trametinib-combination-treatment-a-pooled-analysis-of-individual-patient-data-from-randomised-trials
#3
Georgina V Long, Jean-Jacques Grob, Paul Nathan, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Stephen R Lane, Carmen Mak, Philippe Legenne, Keith T Flaherty, Michael A Davies
BACKGROUND: Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF(V600E)-mutant or BRAF(V600K)-mutant advanced melanoma; however, in many patients the disease progresses, leading to death. With many treatment options available, understanding clinical factors that predict long-term response and survival for treatments is important for optimisation of patient management. We aimed to identify clinical factors associated with long-term response and survival using pooled data from randomised trials of dabrafenib plus trametinib in patients with metastatic BRAF-mutant melanoma...
November 15, 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27863197/programmed-death-ligand-1-expression-and-response-to-the-anti-programmed-death-1-antibody-pembrolizumab-in-melanoma
#4
Adil I Daud, Jedd D Wolchok, Caroline Robert, Wen-Jen Hwu, Jeffrey S Weber, Antoni Ribas, F Stephen Hodi, Anthony M Joshua, Richard Kefford, Peter Hersey, Richard Joseph, Tara C Gangadhar, Roxana Dronca, Amita Patnaik, Hassane Zarour, Charlotte Roach, Grant Toland, Jared K Lunceford, Xiaoyun Nicole Li, Kenneth Emancipator, Marisa Dolled-Filhart, S Peter Kang, Scot Ebbinghaus, Omid Hamid
Purpose Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27650277/a-phase-i-dose-escalation-study-of-tak-733-an-investigational-oral-mek-inhibitor-in-patients-with-advanced-solid-tumors
#5
Alex A Adjei, Patricia LoRusso, Antoni Ribas, Jeffrey A Sosman, Anna Pavlick, Grace K Dy, Xiaofei Zhou, Esha Gangolli, Michelle Kneissl, Stephanie Faucette, Rachel Neuwirth, Viviana Bózon
Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1...
September 21, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27648299/jun-dependency-in-distinct-early-and-late-braf-inhibition-adaptation-states-of-melanoma
#6
Bjoern Titz, Anastasia Lomova, Allison Le, Willy Hugo, Xiangju Kong, Johanna Ten Hoeve, Michael Friedman, Hubing Shi, Gatien Moriceau, Chunying Song, Aayoung Hong, Mohammad Atefi, Richard Li, Evangelia Komisopoulou, Antoni Ribas, Roger S Lo, Thomas G Graeber
A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state...
2016: Cell Discovery
https://www.readbyqxmd.com/read/27622011/combined-treatment-with-dabrafenib-and-trametinib-with-immune-stimulating-antibodies-for-braf-mutant-melanoma
#7
Blanca Homet Moreno, Stephen Mok, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27596353/health-related-quality-of-life-in-the-randomised-keynote-002-study-of-pembrolizumab-versus-chemotherapy-in-patients-with-ipilimumab-refractory-melanoma
#8
Dirk Schadendorf, Reinhard Dummer, Axel Hauschild, Caroline Robert, Omid Hamid, Adil Daud, Alfons van den Eertwegh, Lee Cranmer, Steven O'Day, Igor Puzanov, Jacob Schachter, Christian Blank, April Salama, Carmen Loquai, Janice M Mehnert, Darcy Hille, Scot Ebbinghaus, S Peter Kang, Wei Zhou, Antoni Ribas
BACKGROUND: In KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002. METHODS: Patients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument...
November 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27589875/response-to-programmed-cell-death-1-blockade-in-a-murine-melanoma-syngeneic-model-requires-costimulation-cd4-and-cd8-t-cells
#9
Blanca Homet Moreno, Jesse M Zaretsky, Angel Garcia-Diaz, Jennifer Tsoi, Giulia Parisi, Lidia Robert, Katrina Meeth, Abibatou Ndoye, Marcus Bosenberg, Ashani T Weeraratna, Thomas G Graeber, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAF(V600E)-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAF(V600E) mutation and PTEN loss (BRAF(V600E)/PTEN(-/-))...
October 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27537535/cancer-research-in-the-21st-century
#10
James S Economou, Dennis J Slamon, Antoni Ribas, Michael E Phelps
No abstract text is available yet for this article.
October 2016: Annals of Surgery
https://www.readbyqxmd.com/read/27533633/the-efficacy-of-anti-pd-1-agents-in-acral-and-mucosal-melanoma
#11
Alexander N Shoushtari, Rodrigo R Munhoz, Deborah Kuk, Patrick A Ott, Douglas B Johnson, Katy K Tsai, Suthee Rapisuwon, Zeynep Eroglu, Ryan J Sullivan, Jason J Luke, Tara C Gangadhar, April K S Salama, Varina Clark, Clare Burias, Igor Puzanov, Michael B Atkins, Alain P Algazi, Antoni Ribas, Jedd D Wolchok, Michael A Postow
BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials...
November 15, 2016: Cancer
https://www.readbyqxmd.com/read/27476449/cutaneous-wound-healing-through-paradoxical-mapk-activation-by-braf-inhibitors
#12
Helena Escuin-Ordinas, Shuoran Li, Michael W Xie, Lu Sun, Willy Hugo, Rong Rong Huang, Jing Jiao, Felipe Meira de-Faria, Susan Realegeno, Paige Krystofinski, Ariel Azhdam, Sara Marie D Komenan, Mohammad Atefi, Begoña Comin-Anduix, Matteo Pellegrini, Alistair J Cochran, Robert L Modlin, Harvey R Herschman, Roger S Lo, William H McBride, Tatiana Segura, Antoni Ribas
BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression...
2016: Nature Communications
https://www.readbyqxmd.com/read/27433843/mutations-associated-with-acquired-resistance-to-pd-1-blockade-in-melanoma
#13
Jesse M Zaretsky, Angel Garcia-Diaz, Daniel S Shin, Helena Escuin-Ordinas, Willy Hugo, Siwen Hu-Lieskovan, Davis Y Torrejon, Gabriel Abril-Rodriguez, Salemiz Sandoval, Lucas Barthly, Justin Saco, Blanca Homet Moreno, Riccardo Mezzadra, Bartosz Chmielowski, Kathleen Ruchalski, I Peter Shintaku, Phillip J Sanchez, Cristina Puig-Saus, Grace Cherry, Elizabeth Seja, Xiangju Kong, Jia Pang, Beata Berent-Maoz, Begoña Comin-Anduix, Thomas G Graeber, Paul C Tumeh, Ton N M Schumacher, Roger S Lo, Antoni Ribas
BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later...
September 1, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27428073/phase-ii-randomised-trial-of-autologous-tumour-lysate-dendritic-cell%C3%A2-plus-best-supportive-care%C3%A2-compared-with-best-supportive-care-in-pre-treated-advanced-colorectal-cancer-patients
#14
Miguel Caballero-Baños, Daniel Benitez-Ribas, Jaime Tabera, Sara Varea, Ramon Vilana, Luis Bianchi, Juan Ramón Ayuso, Mario Pagés, Gemma Carrera, Miriam Cuatrecasas, Marta Martin-Richard, Joan Cid, Miguel Lozano, Antoni Castells, Xabier García-Albéniz, Joan Maurel, Ramon Vilella
BACKGROUND: Autologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, were randomised to EA versus CA...
September 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27383789/corrigendum-sfrp2-in-the-aged-microenvironment-drives-melanoma-metastasis-and-therapy-resistance
#15
Amanpreet Kaur, Marie R Webster, Katie Marchbank, Reeti Behera, Abibatou Ndoye, Curtis H Kugel, Vanessa M Dang, Jessica Appleton, Michael P O'Connell, Phil Cheng, Alexander A Valiga, Rachel Morissette, Nazli B McDonnell, Luigi Ferrucci, Andrew V Kossenkov, Katrina Meeth, Hsin-Yao Tang, Xiangfan Yin, William H Wood, Elin Lehrmann, Kevin G Becker, Keith T Flaherty, Dennie T Frederick, Jennifer A Wargo, Zachary A Cooper, Michael T Tetzlaff, Courtney Hudgens, Katherine M Aird, Rugang Zhang, Xiaowei Xu, Qin Liu, Edmund Bartlett, Giorgos Karakousis, Zeynep Eroglu, Roger S Lo, Matthew Chan, Alexander M Menzies, Georgina V Long, Douglas B Johnson, Jeffrey Sosman, Bastian Schilling, Dirk Schadendorf, David W Speicher, Marcus Bosenberg, Antoni Ribas, Ashani T Weeraratna
No abstract text is available yet for this article.
July 6, 2016: Nature
https://www.readbyqxmd.com/read/27273450/craf-r391w-is-a-melanoma-driver-oncogene
#16
Mohammad Atefi, Bjoern Titz, Jennifer Tsoi, Earl Avramis, Allison Le, Charles Ng, Anastasia Lomova, Amanda Lassen, Michael Friedman, Bartosz Chmielowski, Antoni Ribas, Thomas G Graeber
Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27270265/-gesida-quality-care-indicators-associated-with-mortality-and-hospital-admission-for-the-care-of-persons-infected-by-hiv-aids
#17
Elena Delgado-Mejía, Guillem Frontera-Juan, Javier Murillas-Angoiti, Antoni Abdon Campins-Roselló, Leire Gil-Alonso, María Peñaranda-Vera, María Angels Ribas Del Blanco, María Luisa Martín-Pena, Melchor Riera-Jaume
INTRODUCTION: In 2010, the AIDS Study Group (Grupo de Estudio del SIDA [GESIDA]) developed 66 quality care indicators. The aim of this study is to determine which of these indicators are associated with mortality and hospital admission, and to perform a preliminary assessment of a prediction rule for mortality and hospital admission in patients on treatment and follow-up. METHODS: A retrospective cohort study was conducted in the Hospital Universitario Son Espases (Palma de Mallorca, Spain)...
June 4, 2016: Enfermedades Infecciosas y Microbiología Clínica
https://www.readbyqxmd.com/read/27151852/cancer-immunology-the-cancer-immunogram
#18
Christian U Blank, John B Haanen, Antoni Ribas, Ton N Schumacher
No abstract text is available yet for this article.
May 6, 2016: Science
https://www.readbyqxmd.com/read/27092830/association-of-pembrolizumab-with-tumor-response-and-survival-among-patients-with-advanced-melanoma
#19
MULTICENTER STUDY
Antoni Ribas, Omid Hamid, Adil Daud, F Stephen Hodi, Jedd D Wolchok, Richard Kefford, Anthony M Joshua, Amita Patnaik, Wen-Jen Hwu, Jeffrey S Weber, Tara C Gangadhar, Peter Hersey, Roxana Dronca, Richard W Joseph, Hassane Zarour, Bartosz Chmielowski, Donald P Lawrence, Alain Algazi, Naiyer A Rizvi, Brianna Hoffner, Christine Mateus, Kevin Gergich, Jill A Lindia, Maxine Giannotti, Xiaoyun Nicole Li, Scot Ebbinghaus, S Peter Kang, Caroline Robert
IMPORTANCE: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. OBJECTIVE: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. DESIGN, SETTINGS, AND PARTICIPANTS: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months...
April 19, 2016: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/27087480/the-state-of-melanoma-challenges-and-opportunities
#20
Glenn Merlino, Meenhard Herlyn, David E Fisher, Boris C Bastian, Keith T Flaherty, Michael A Davies, Jennifer A Wargo, Clara Curiel-Lewandrowski, Michael J Weber, Sancy A Leachman, Maria S Soengas, Martin McMahon, J William Harbour, Susan M Swetter, Andrew E Aplin, Michael B Atkins, Marcus W Bosenberg, Reinhard Dummer, Jeffrey E Gershenwald, Allan C Halpern, Dorothee Herlyn, Giorgos C Karakousis, John M Kirkwood, Michael Krauthammer, Roger S Lo, Georgina V Long, Grant McArthur, Antoni Ribas, Lynn Schuchter, Jeffrey A Sosman, Keiran S Smalley, Patricia Steeg, Nancy E Thomas, Hensin Tsao, Thomas Tueting, Ashani Weeraratna, George Xu, Randy Lomax, Alison Martin, Steve Silverstein, Tim Turnham, Ze'ev A Ronai
The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November...
July 2016: Pigment Cell & Melanoma Research
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