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https://www.readbyqxmd.com/read/28514453/chromatin-states-define-tumour-specific-t-cell-dysfunction-and-reprogramming
#1
Mary Philip, Lauren Fairchild, Liping Sun, Ellen L Horste, Steven Camara, Mojdeh Shakiba, Andrew C Scott, Agnes Viale, Peter Lauer, Taha Merghoub, Matthew D Hellmann, Jedd D Wolchok, Christina S Leslie, Andrea Schietinger
Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1(hi) dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1(hi) tumour-infiltrating CD8 T cells...
May 17, 2017: Nature
https://www.readbyqxmd.com/read/28506536/checkpoint-inhibition-and-melanoma-considerations-in-treating-the-older-adult
#2
REVIEW
Claire F Friedman, Jedd D Wolchok
The incidence of melanoma and associated mortality rate from advanced disease in older adults is increasing over time. Checkpoint inhibitors have demonstrated a survival benefit for the treatment of stage IV or unresectable stage III disease and have become one of the standards of care. Data suggests that adults aged 65 and older benefit from treatment with checkpoint inhibitors without an increased incidence in adverse events. However, clinicians should be aware of the potential side effects of this class of medications and how to manage them in older adults...
May 11, 2017: Journal of Geriatric Oncology
https://www.readbyqxmd.com/read/28397821/t-cell-invigoration-to-tumour-burden-ratio-associated-with-anti-pd-1-response
#3
Alexander C Huang, Michael A Postow, Robert J Orlowski, Rosemarie Mick, Bertram Bengsch, Sasikanth Manne, Wei Xu, Shannon Harmon, Josephine R Giles, Brandon Wenz, Matthew Adamow, Deborah Kuk, Katherine S Panageas, Cristina Carrera, Phillip Wong, Felix Quagliarello, Bradley Wubbenhorst, Kurt D'Andrea, Kristen E Pauken, Ramin S Herati, Ryan P Staupe, Jason M Schenkel, Suzanne McGettigan, Shawn Kothari, Sangeeth M George, Robert H Vonderheide, Ravi K Amaravadi, Giorgos C Karakousis, Lynn M Schuchter, Xiaowei Xu, Katherine L Nathanson, Jedd D Wolchok, Tara C Gangadhar, E John Wherry
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells)...
May 4, 2017: Nature
https://www.readbyqxmd.com/read/28388418/inhibiting-dna-methylation-causes-an-interferon-response-in-cancer-via-dsrna-including-endogenous-retroviruses
#4
Katherine B Chiappinelli, Pamela L Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S Rote, Leslie M Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Dennis J Slamon, Jedd D Wolchok, Drew M Pardoll, Matthias W Beckmann, Cynthia A Zahnow, Taha Merghoub, Timothy A Chan, Stephen B Baylin, Reiner Strick
No abstract text is available yet for this article.
April 6, 2017: Cell
https://www.readbyqxmd.com/read/28356222/neutrophil-to-lymphocyte-ratio-is-associated-with-outcome-during-ipilimumab-treatment
#5
Michael R Cassidy, Rachel E Wolchok, Junting Zheng, Katherine S Panageas, Jedd D Wolchok, Daniel Coit, Michael A Postow, Charlotte Ariyan
BACKGROUND: Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. METHODS: Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified...
April 2017: EBioMedicine
https://www.readbyqxmd.com/read/28271869/irecist-guidelines-for-response-criteria-for-use-in-trials-testing-immunotherapeutics
#6
REVIEW
Lesley Seymour, Jan Bogaerts, Andrea Perrone, Robert Ford, Lawrence H Schwartz, Sumithra Mandrekar, Nancy U Lin, Saskia Litière, Janet Dancey, Alice Chen, F Stephen Hodi, Patrick Therasse, Otto S Hoekstra, Lalitha K Shankar, Jedd D Wolchok, Marcus Ballinger, Caroline Caramella, Elisabeth G E de Vries
Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline...
March 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28247127/patient-perspectives-on-ipilimumab-across-the-melanoma-treatment-trajectory
#7
Elyse Shuk, Alexander N Shoushtari, Jason Luke, Michael A Postow, Maggie Callahan, James J Harding, Katherine G Roth, Marisa Flavin, Adrian Granobles, Jana Christian, Geoffrey Gold, Maria Schoenhammer, Mallorie Gordon, Nicholas Cimaglia, Robert Dyson, Noah Goodman-Davis, Marta N Colgan, Itisha S Jefferson, Rodrigo Munhoz, Sandra D'Angelo, Jedd Wolchok, Paul Chapman, Ping Chi, Richard D Carvajal, Jennifer L Hay
PURPOSE: Ipilimumab was the first FDA-approved agent for advanced melanoma to improve survival and represents a paradigm shift in melanoma and cancer treatment. Its unique toxicity profile and kinetics of treatment response raise novel patient education challenges. We assessed patient perceptions of ipilimumab therapy across the treatment trajectory. METHODS: Four patient cohorts were assessed at different time points relative to treatment initiation: (1) prior to initiation of ipilimumab (n = 10), (2) at weeks 10-12 before restaging studies (n = 11), (3) at week 12 following restaging studies indicating progression of disease (n = 10), and (4) at week 12 following restaging studies indicating either a radiographic response or disease stability (n = 10)...
March 1, 2017: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
https://www.readbyqxmd.com/read/28239469/combination-immunotherapy-a-road-map
#8
REVIEW
Patrick A Ott, F Stephen Hodi, Howard L Kaufman, Jon M Wigginton, Jedd D Wolchok
Cancer immunotherapy and in particular monoclonal antibodies blocking the inhibitory programed cell death 1 pathway (PD-1/PD-L1) have made a significant impact on the treatment of cancer patients in recent years. However, despite the remarkable clinical efficacy of these agents in a number of malignancies, it has become clear that they are not sufficiently active for many patients. Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC), has highlighted the potential to further enhance the clinical benefits of monotherapies by combining agents with synergistic mechanisms of action...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28194010/intratumoral-modulation-of-the-inducible-co-stimulator-icos-by-recombinant-oncolytic-virus-promotes-systemic-anti-tumour-immunity
#9
Dmitriy Zamarin, Rikke B Holmgaard, Jacob Ricca, Tamar Plitt, Peter Palese, Padmanee Sharma, Taha Merghoub, Jedd D Wolchok, James P Allison
Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, although the appropriate targets for intratumoral immunomodulation using this strategy are not known. Here we find that intratumoral therapy with Newcastle disease virus (NDV), in addition to the activation of innate immunity, upregulates the expression of T-cell co-stimulatory receptors, with the inducible co-stimulator (ICOS) being most notable. To explore ICOS as a direct target in the tumour, we engineered a recombinant NDV-expressing ICOS ligand (NDV-ICOSL)...
February 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28185198/validation-of-anti-mouse-pdl-1-goat-polyclonal-antibody-staining-with-mouse-pdl-1-in-situ-hybridization-on-adjacent-sections-of-cell-pellets-and-mouse-tumors
#10
Jacob Ricca, Mesruh Turkekul, Afsar Barlas, Dmitry Yarilin, Sho Fujisawa, Ning Fan, Matthew Brendel, Dmitriy Zamarin, Jedd D Wolchok, Katia Manova-Todorova
Finding a valid antibody to detect mouse programmed death ligand 1 (PDL-1) by immunohistochemistry or immunofluorescence staining has been notoriously difficult. Successful validation of an antibody requires the use of multiple detection methods with the ability to compare appropriate positive and negative controls. Here, we describe in detail the protocols used to validate a mouse-specific PDL-1 antibody used in immunohistochemistry staining with an mRNA in situ hybridization on adjacent sections of mouse B16 tumor...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28167454/peripheral-cd8-effector-memory-type-1-t-cells-correlate-with-outcome-in-ipilimumab-treated-stage-iv-melanoma-patients
#11
Kilian Wistuba-Hamprecht, Alexander Martens, Florian Heubach, Emanuela Romano, Marnix Geukes Foppen, Jianda Yuan, Michael Postow, Phillip Wong, Domenico Mallardo, Bastian Schilling, Anna Maria Di Giacomo, Amir Khammari, Brigitte Dreno, Michele Maio, Dirk Schadendorf, Paolo A Ascierto, Jedd D Wolchok, Christian U Blank, Claus Garbe, Graham Pawelec, Benjamin Weide
The role of the assessment of peripheral T-cell phenotypes in predicting overall survival (OS) after ipilimumab treatment is unclear. Here, we analysed mononuclear cells in the blood before and at different time points during treatment with ipilimumab in 137 late-stage melanoma patients. The proportions of baseline naïve and memory T-cells were measured by flow cytometry and correlated with OS, with an emphasis on PD-1 expression. High frequencies (>13%) of CD8 effector-memory type 1 (EM1) T-cells at baseline correlated with longer OS (p = 0...
March 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28162999/health-related-quality-of-life-with-adjuvant-ipilimumab-versus-placebo-after-complete-resection-of-high-risk-stage-iii-melanoma-eortc-18071-secondary-outcomes-of-a-multinational-randomised-double-blind-phase-3-trial
#12
Corneel Coens, Stefan Suciu, Vanna Chiarion-Sileni, Jean-Jacques Grob, Reinhard Dummer, Jedd D Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A Ascierto, Jon M Richards, Celeste Lebbé, Virginia Ferraresi, Michael Smylie, Jeffrey S Weber, Michele Maio, Andrew Bottomley, Srividya Kotapati, Veerle de Pril, Alessandro Testori, Alexander M M Eggermont
BACKGROUND: The EORTC 18071 phase 3 trial compared adjuvant ipilimumab with placebo in patients with stage III melanoma. The primary endpoint, recurrence-free survival, was significantly longer in the ipilimumab group than in the placebo group. Investigator-reported toxic effects of ipilimumab consisted mainly of skin, gastrointestinal, endocrine, and hepatic immune-related adverse events. Adjuvant treatment with ipilimumab in this setting was approved in October, 2014, by the US Food and Drug Administration based on the results of the primary outcome of this trial...
March 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28106152/cancer-immunotherapy-immune-checkpoint-blockade-and-associated-endocrinopathies
#13
REVIEW
David J Byun, Jedd D Wolchok, Lynne M Rosenberg, Monica Girotra
Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease...
April 2017: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/28068177/safety-profile-of-nivolumab-monotherapy-a-pooled-analysis-of-patients-with-advanced-melanoma
#14
Jeffrey S Weber, F Stephen Hodi, Jedd D Wolchok, Suzanne L Topalian, Dirk Schadendorf, James Larkin, Mario Sznol, Georgina V Long, Hewei Li, Ian M Waxman, Joel Jiang, Caroline Robert
Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy...
March 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28056206/efficacy-and-safety-of-nivolumab-alone-or-in-combination-with-ipilimumab-in-patients-with-mucosal-melanoma-a-pooled-analysis
#15
Sandra P D'Angelo, James Larkin, Jeffrey A Sosman, Celeste Lebbé, Benjamin Brady, Bart Neyns, Henrik Schmidt, Jessica C Hassel, F Stephen Hodi, Paul Lorigan, Kerry J Savage, Wilson H Miller, Peter Mohr, Ivan Marquez-Rodas, Julie Charles, Martin Kaatz, Mario Sznol, Jeffrey S Weber, Alexander N Shoushtari, Mary Ruisi, Joel Jiang, Jedd D Wolchok
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma...
January 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28040701/thinking-critically-about-classifying-adverse-events-incidence-of-pancreatitis-in-patients-treated-with-nivolumab-ipilimumab
#16
Claire F Friedman, Varina Clark, Andrew V Raikhel, Tim Barz, Alexander N Shoushtari, Parisa Momtaz, Margaret K Callahan, Jedd D Wolchok, Paul B Chapman, Matthew D Hellmann, Michael A Postow
The Common Terminology Criteria for Adverse Events (CTCAE) were developed to document the adverse effects of chemotherapy but are now also used to document immune-related adverse events (irAE). Characterization of irAE by the CTCAE has implications for determining dose-limiting toxicity (DLT) and, consequently, the recommended phase II dose (RP2D) of investigational agents. In the phase I trial of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT that informed the RP2D. We performed a retrospective study of 119 patients with melanoma who were treated at Memorial Sloan Kettering Cancer Center with the combination of nivolumab + ipilimumab to investigate the relationship between asymptomatic grade 3 or higher increases in amylase and/or lipase and pancreatitis, a known irAE...
April 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27982025/morphological-characterization-of-colorectal-cancers-in-the-cancer-genome-atlas-reveals-distinct-morphology-molecular-associations-clinical-and-biological-implications
#17
Jinru Shia, Nikolaus Schultz, Deborah Kuk, Efsevia Vakiani, Sumit Middha, Neil H Segal, Jaclyn F Hechtman, Michael F Berger, Zsofia K Stadler, Martin R Weiser, Jedd D Wolchok, C Richard Boland, Mithat Gönen, David S Klimstra
The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population...
April 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/27956380/somatic-mutations-and-neoepitope-homology-in-melanomas-treated-with-ctla-4-blockade
#18
Tavi Nathanson, Arun Ahuja, Alexander Rubinsteyn, Bulent Arman Aksoy, Matthew D Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd D Wolchok, Alexandra Snyder, Jeff Hammerbacher
Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients...
January 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/27923027/corrigendum-melanoma-exosomes-educate-bone-marrow-progenitor-cells-toward-a-pro-metastatic-phenotype-through-met
#19
Héctor Peinado, Maša Alecˇković, Simon Lavotshkin, Irina Matei, Bruno Costa-Silva, Gema Moreno-Bueno, Marta Hergueta-Redondo, Caitlin Williams, Guillermo García-Santos, Cyrus M Ghajar, Ayuko Nitadori-Hoshino, Caitlin Hoffman, Karen Badal, Benjamin A Garcia, Margaret K Callahan, Jianda Yuan, Vilma R Martins, Johan Skog, Rosandra N Kaplan, Mary S Brady, Jedd D Wolchok, Paul B Chapman, Yibin Kang, Jacqueline Bromberg, David Lyden
No abstract text is available yet for this article.
December 6, 2016: Nature Medicine
https://www.readbyqxmd.com/read/27863197/programmed-death-ligand-1-expression-and-response-to-the-anti-programmed-death-1-antibody-pembrolizumab-in-melanoma
#20
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
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