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https://www.readbyqxmd.com/read/28106152/cancer-immunotherapy-immune-checkpoint-blockade-and-associated-endocrinopathies
#1
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...
January 20, 2017: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/28068177/safety-profile-of-nivolumab-monotherapy-a-pooled-analysis-of-patients-with-advanced-melanoma
#2
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...
November 14, 2016: 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
#3
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
#4
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
#5
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...
December 16, 2016: 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
#6
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...
December 12, 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27923027/corrigendum-melanoma-exosomes-educate-bone-marrow-progenitor-cells-toward-a-pro-metastatic-phenotype-through-met
#7
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
#8
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/27828943/overcoming-resistance-to-checkpoint-blockade-therapy-by-targeting-pi3k%C3%AE-in-myeloid-cells
#9
Olivier De Henau, Matthew Rausch, David Winkler, Luis Felipe Campesato, Cailian Liu, Daniel Hirschhorn Cymerman, Sadna Budhu, Arnab Ghosh, Melissa Pink, Jeremy Tchaicha, Mark Douglas, Thomas Tibbitts, Sujata Sharma, Jennifer Proctor, Nicole Kosmider, Kerry White, Howard Stern, John Soglia, Julian Adams, Vito J Palombella, Karen McGovern, Jeffery L Kutok, Jedd D Wolchok, Taha Merghoub
Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity...
November 17, 2016: Nature
https://www.readbyqxmd.com/read/27807100/successful-treatment-of-a-patient-with-glioblastoma-and-a-germline-pole-mutation-where-next
#10
Alexandra Snyder, Jedd D Wolchok
Hypermutation and elevated neoantigen count in glioblastoma occurred in a patient harboring a germline POLE mutation and are associated with a clinical and antitumor immune response to PD-1 blockade. Cancer Discov; 6(11); 1210-11. ©2016 AACR.See related article by Johanns et al., p. 1230.
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27797971/an-open-label-dose-escalation-phase-i-study-of-anti-tyrp1-monoclonal-antibody-imc-20d7s-for-patients-with-relapsed-or-refractory-melanoma
#11
Danny N Khalil, Michael A Postow, Nageatte Ibrahim, Dale L Ludwig, Jan Cosaert, Siva Rama Prasad Kambhampati, Shande Tang, Dmitri Grebennik, John Sae Wook Kauh, Heinz-Josef Lenz, Keith T Flaherty, F Stephen Hodi, Donald P Lawrence, Jedd D Wolchok
PURPOSE: Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S. EXPERIMENTAL DESIGN: The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S...
November 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27792058/clinical-features-and-response-to-systemic-therapy-in-a-historical-cohort-of-advanced-or-unresectable-mucosal-melanoma
#12
Alexander N Shoushtari, Mark J Bluth, Debra A Goldman, Christiana Bitas, Robert A Lefkowitz, Michael A Postow, Rodrigo R Munhoz, Gauri Buchar, Robert H Hester, Jacqueline A Romero, Laura J Fitzpatrick, Martin R Weiser, Katherine S Panageas, Jedd D Wolchok, Paul B Chapman, Richard D Carvajal
There are very few data available regarding the pattern of first metastases in resected mucosal melanomas (MMs) as well as the response of advanced MM to cytotoxic therapy. A retrospective, single-institution cohort was assembled of all patients with advanced/unresectable MM between 1995 and 2012 who had received systemic therapy with available imaging (N=81). Responses to first-line and second-line systemic therapy were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The relationship between response, overall survival, and clinical covariates was investigated using Cox proportional hazards regression...
February 2017: Melanoma Research
https://www.readbyqxmd.com/read/27717298/prolonged-survival-in-stage-iii-melanoma-with-ipilimumab-adjuvant-therapy
#13
RANDOMIZED CONTROLLED TRIAL
Alexander M M Eggermont, Vanna Chiarion-Sileni, Jean-Jacques Grob, Reinhard Dummer, Jedd D Wolchok, Henrik Schmidt, Omid Hamid, Caroline Robert, Paolo A Ascierto, Jon M Richards, Céleste Lebbé, Virginia Ferraresi, Michael Smylie, Jeffrey S Weber, Michele Maio, Lars Bastholt, Laurent Mortier, Luc Thomas, Saad Tahir, Axel Hauschild, Jessica C Hassel, F Stephen Hodi, Corina Taitt, Veerle de Pril, Gaetan de Schaetzen, Stefan Suciu, Alessandro Testori
Background On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. Methods After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred...
November 10, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27680026/kinase-regulation-of-human-mhc-class-i-molecule-expression-on-cancer-cells
#14
Elliott J Brea, Claire Y Oh, Eusebio Manchado, Sadna Budhu, Ron S Gejman, George Mo, Patrizia Mondello, James E Han, Casey A Jarvis, David Ulmert, Qing Xiang, Aaron Y Chang, Ralph J Garippa, Taha Merghoub, Jedd D Wolchok, Neal Rosen, Scott W Lowe, David A Scheinberg
The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8(+) T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped...
November 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27646942/pneumonitis-in-patients-treated-with-anti-programmed-death-1-programmed-death-ligand-1-therapy
#15
Jarushka Naidoo, Xuan Wang, Kaitlin M Woo, Tunc Iyriboz, Darragh Halpenny, Jane Cunningham, Jamie E Chaft, Neil H Segal, Margaret K Callahan, Alexander M Lesokhin, Jonathan Rosenberg, Martin Voss, Charles M Rudin, Hira Rizvi, Xue Hou, Katherine Rodriguez, Melanie Albano, Ruth-Ann Gordon, Charles Leduc, Natasha Rekhtman, Bianca Harris, Alexander M Menzies, Alexander D Guminski, Matteo S Carlino, Benjamin Y Kong, Jedd D Wolchok, Michael A Postow, Georgina V Long, Matthew D Hellmann
PURPOSE: Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. METHODS: Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015)...
September 19, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27622997/combined-nivolumab-and-ipilimumab-versus-ipilimumab-alone-in-patients-with-advanced-melanoma-2-year-overall-survival-outcomes-in-a-multicentre-randomised-controlled-phase-2-trial
#16
F Stephen Hodi, Jason Chesney, Anna C Pavlick, Caroline Robert, Kenneth F Grossmann, David F McDermott, Gerald P Linette, Nicolas Meyer, Jeffrey K Giguere, Sanjiv S Agarwala, Montaser Shaheen, Marc S Ernstoff, David R Minor, April K Salama, Matthew H Taylor, Patrick A Ott, Christine Horak, Paul Gagnier, Joel Jiang, Jedd D Wolchok, Michael A Postow
BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma...
November 2016: Lancet Oncology
https://www.readbyqxmd.com/read/27622016/timing-of-csf-1-csf-1r-signaling-blockade-is-critical-to-improving-responses-to-ctla-4-based-immunotherapy
#17
Rikke B Holmgaard, Alexandra Brachfeld, Billel Gasmi, David R Jones, Marissa Mattar, Thompson Doman, Mary Murphy, David Schaer, Jedd D Wolchok, Taha Merghoub
UNLABELLED: Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade...
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27587469/deep-sequencing-of-t-cell-receptor-dna-as-a-biomarker-of-clonally-expanded-tils-in-breast-cancer-after-immunotherapy
#18
David B Page, Jianda Yuan, David Redmond, Y Hanna Wen, Jeremy C Durack, Ryan Emerson, Stephen Solomon, Zhiwan Dong, Phillip Wong, Christopher Comstock, Adi Diab, Janice Sung, Majid Maybody, Elizabeth Morris, Edi Brogi, Monica Morrow, Virgilio Sacchini, Olivier Elemento, Harlan Robins, Sujata Patil, James P Allison, Jedd D Wolchok, Clifford Hudis, Larry Norton, Heather L McArthur
In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab...
October 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27566765/a-pilot-study-of-preoperative-single-dose-ipilimumab-and-or-cryoablation-in-women-with-early-stage-breast-cancer-with-comprehensive-immune-profiling
#19
Heather L McArthur, Adi Diab, David B Page, Jianda Yuan, Stephen B Solomon, Virgilio Sacchini, Christopher Comstock, Jeremy C Durack, Majid Maybody, Janice Sung, Arielle Ginsberg, Phillip Wong, Afsar Barlas, Zhiwan Dong, Chunjun Zhao, Brian Blum, Sujata Patil, Deirdre Neville, Elizabeth A Comen, Elizabeth A Morris, Alan Kotin, Edi Brogi, Y Hannah Wen, Monica Morrow, Mario E Lacouture, Padmanee Sharma, James P Allison, Clifford A Hudis, Jedd D Wolchok, Larry Norton
PURPOSE: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. EXPERIMENTAL DESIGN: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27533633/the-efficacy-of-anti-pd-1-agents-in-acral-and-mucosal-melanoma
#20
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
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