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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...
October 7, 2016: New England Journal of Medicine
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-I) 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...
September 28, 2016: Cancer Immunology Research
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
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...
September 9, 2016: Lancet Oncology
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
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
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 Comen, Elizabeth A Morris, Alan Kotin, Edi Brogi, Y Hannah Wen, Monica Morrow, Mario E Lacouture, Padmanee Sharma, James P Allision, Clifford A Hudis, Jedd D Wolchok, Larry Norton
PURPOSE: To assess the safety and tolerability of pre-operative 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 pre-operative tumor cryoablation (n=7), single-dose ipilimumab at 10mg/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...
August 26, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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...
August 17, 2016: Cancer
F Stephen Hodi, Jedd D Wolchok
No abstract text is available yet for this article.
October 1, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Kilian Wistuba-Hamprecht, Alexander Martens, Karin Haehnel, Marnix Geukes Foppen, Jianda Yuan, Michael A Postow, Phillip Wong, Emanuela Romano, Amir Khammari, Brigitte Dreno, Mariaelena Capone, Paolo A Ascierto, Ilja Demuth, Elisabeth Steinhagen-Thiessen, Anis Larbi, Bastian Schilling, Dirk Schadendorf, Jedd D Wolchok, Christian U Blank, Graham Pawelec, Claus Garbe, Benjamin Weide
Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0...
September 2016: European Journal of Cancer
Lavoisier Ramos-Espiritu, Ana Diaz, Charlee Nardin, Anthony J Saviola, Fiona Shaw, Tamar Plitt, Xia Yang, Jedd Wolchok, Edyta C Pirog, Garrett Desman, Andrea Sboner, Tuo Zhang, Jenny Xiang, Taha Merghoub, Lonny R Levin, Jochen Buck, Jonathan H Zippin
cAMP signaling pathways can both stimulate and inhibit the development of cancer; however, the sources of cAMP important for tumorigenesis remain poorly understood. Soluble adenylyl cyclase (sAC) is a non-canonical, evolutionarily conserved, nutrient- and pH-sensing source of cAMP. sAC has been implicated in the metastatic potential of certain cancers, and it is differentially localized in human cancers as compared to benign tissues. We now show that sAC expression is reduced in many human cancers. Loss of sAC increases cellular transformation in vitro and malignant progression in vivo...
June 15, 2016: Oncotarget
Matthew Hellmann, Naiyer Rizvi, Jedd D Wolchok, Timothy A Chan
The recent successes of immune checkpoint therapies have established a new era for the treatment of patients with cancer, yet the predictors of response remain largely undetermined. We recently demonstrated that the genomic landscape of lung cancers substantially influences the response to programmed cell death 1 receptor (PD-1) blockade, providing new insights into the molecular determinants of the response to immunotherapy.
January 2016: Molecular & Cellular Oncology
Frank B Cortazar, Kristen A Marrone, Megan L Troxell, Kenneth M Ralto, Melanie P Hoenig, Julie R Brahmer, Dung T Le, Evan J Lipson, Ilya G Glezerman, Jedd Wolchok, Lynn D Cornell, Paul Feldman, Michael B Stokes, Sarah A Zapata, F Stephen Hodi, Patrick A Ott, Michifumi Yamashita, David E Leaf
Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0...
September 2016: Kidney International
Aude G Chapuis, Ilana M Roberts, John A Thompson, Kim A Margolin, Shailender Bhatia, Sylvia M Lee, Heather L Sloan, Ivy P Lai, Erik A Farrar, Felecia Wagener, Kendall C Shibuya, Jianhong Cao, Jedd D Wolchok, Philip D Greenberg, Cassian Yee
PURPOSE: Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs...
June 6, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Aude G Chapuis, Sylvia M Lee, John A Thompson, Ilana M Roberts, Kim A Margolin, Shailender Bhatia, Heather L Sloan, Ivy Lai, Felecia Wagener, Kendall Shibuya, Jianhong Cao, Jedd D Wolchok, Philip D Greenberg, Cassian Yee
Adoptive transfer of peripheral blood-derived, melanoma-reactive CD8(+) cytotoxic T lymphocytes (CTLs) alone is generally insufficient to eliminate bulky tumors. Similarly, monotherapy with anti-CTLA4 infrequently yields sustained remissions in patients with metastatic melanoma. We postulated that a bolus of enhanced IL-21-primed polyclonal antigen-specific CTL combined with CTLA4 blockade might boost antitumor efficacy. In this first-in-human case study, the combination successfully led to a durable complete remission (CR) in a patient whose disease was refractory to both monoclonal CTL and anti-CTLA4...
June 27, 2016: Journal of Experimental Medicine
Lawrence H Schwartz, Lesley Seymour, Saskia Litière, Robert Ford, Stephen Gwyther, Sumithra Mandrekar, Lalitha Shankar, Jan Bogaerts, Alice Chen, Janet Dancey, Wendy Hayes, F Stephen Hodi, Otto S Hoekstra, Erich P Huang, Nancy Lin, Yan Liu, Patrick Therasse, Jedd D Wolchok, Elisabeth de Vries
Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users...
July 2016: European Journal of Cancer
Rikke B Holmgaard, Dmitriy Zamarin, Alexander Lesokhin, Taha Merghoub, Jedd D Wolchok
Tumor indoleamine 2,3-dioxygenase (IDO) promotes immunosuppression by direct action on effector T cells and Tregs and through recruitment, expansion and activation of myeloid-derived suppressor cells (MDSCs). Targeting of MDSCs is clinically being explored as a therapeutic strategy, though optimal targeting strategies and biomarkers predictive of response are presently unknown. Maturation and tumor recruitment of MDSCs are dependent on signaling through the receptor tyrosine kinase CSF-1R on myeloid cells. Here, we show that MDSCs are the critical cell population in IDO-expressing B16 tumors in mediating accelerated tumor outgrowth and resistance to immunotherapy...
April 2016: EBioMedicine
Margaret K Callahan, Michael A Postow, Jedd D Wolchok
Checkpoint-blocking antibodies can generate potent anti-tumor responses by encouraging the immune system to seek and destroy cancer cells. At this time, the United States Food and Drug Administration has approved three checkpoint-blocking antibodies in three disease indications, and additional approvals are expected to broaden the clinical scope of immunotherapy. Herein, we review the clinical development of CTLA-4-, PD-1-, and PD-L1-blocking antibodies across tumor types and briefly discuss areas of active investigation of potential biomarkers...
May 17, 2016: Immunity
Lawrence H Schwartz, Saskia Litière, Elisabeth de Vries, Robert Ford, Stephen Gwyther, Sumithra Mandrekar, Lalitha Shankar, Jan Bogaerts, Alice Chen, Janet Dancey, Wendy Hayes, F Stephen Hodi, Otto S Hoekstra, Erich P Huang, Nancy Lin, Yan Liu, Patrick Therasse, Jedd D Wolchok, Lesley Seymour
The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression...
July 2016: European Journal of Cancer
Benjamin Weide, Alexander Martens, Jessica C Hassel, Carola Berking, Michael A Postow, Kees Bisschop, Ester Simeone, Johanna Mangana, Bastian Schilling, Anna-Maria Di Giacomo, Nicole Brenner, Katharina C Kähler, Lucie Heinzerling, Ralf Gutzmer, Armin Bender, Christoffer Gebhardt, Emanuela Romano, Friedegund Meier, Peter Martus, Michele Maio, Christian U Blank, Dirk Schadendorf, Reinhard Dummer, Paolo A Ascierto, Geke A Hospers, Claus Garbe, Jedd D Wolchok
PURPOSE: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) following pembrolizumab treatment in melanoma patients. EXPERIMENTAL DESIGN: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab...
May 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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