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https://www.readbyqxmd.com/read/28915085/pooled-analysis-safety-profile-of-nivolumab-and-ipilimumab-combination-therapy-in-patients-with-advanced-melanoma
#1
Mario Sznol, Pier Francesco Ferrucci, David Hogg, Michael B Atkins, Pascal Wolter, Massimo Guidoboni, Celeste Lebbé, John M Kirkwood, Jacob Schachter, Gregory A Daniels, Jessica Hassel, Jonathan Cebon, Winald Gerritsen, Victoria Atkinson, Luc Thomas, John McCaffrey, Derek Power, Dana Walker, Rafia Bhore, Joel Jiang, F Stephen Hodi, Jedd D Wolchok
Purpose The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management...
September 15, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28889792/overall-survival-with-combined-nivolumab-and-ipilimumab-in-advanced-melanoma
#2
Jedd D Wolchok, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean-Jacques Grob, C Lance Cowey, Christopher D Lao, John Wagstaff, Dirk Schadendorf, Pier F Ferrucci, Michael Smylie, Reinhard Dummer, Andrew Hill, David Hogg, John Haanen, Matteo S Carlino, Oliver Bechter, Michele Maio, Ivan Marquez-Rodas, Massimo Guidoboni, Grant McArthur, Celeste Lebbé, Paolo A Ascierto, Georgina V Long, Jonathan Cebon, Jeffrey Sosman, Michael A Postow, Margaret K Callahan, Dana Walker, Linda Rollin, Rafia Bhore, F Stephen Hodi, James Larkin
Background Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. Methods We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent...
September 11, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28851824/blockade-of-surface-bound-tgf-%C3%AE-on-regulatory-t-cells-abrogates-suppression-of-effector-t-cell-function-in-the-tumor-microenvironment
#3
Sadna Budhu, David A Schaer, Yongbiao Li, Ricardo Toledo-Crow, Katherine Panageas, Xia Yang, Hong Zhong, Alan N Houghton, Samuel C Silverstein, Taha Merghoub, Jedd D Wolchok
Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8(+) T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system...
August 29, 2017: Science Signaling
https://www.readbyqxmd.com/read/28841418/heterogeneous-tumor-immune-microenvironments-among-differentially-growing-metastases-in-an-ovarian-cancer-patient
#4
Alejandro Jiménez-Sánchez, Danish Memon, Stephane Pourpe, Harini Veeraraghavan, Yanyun Li, Hebert Alberto Vargas, Michael B Gill, Kay J Park, Oliver Zivanovic, Jason Konner, Jacob Ricca, Dmitriy Zamarin, Tyler Walther, Carol Aghajanian, Jedd D Wolchok, Evis Sala, Taha Merghoub, Alexandra Snyder, Martin L Miller
We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8(+) and CD4(+) T cells and exhibited oligoclonal expansion of specific T cell subsets...
August 24, 2017: Cell
https://www.readbyqxmd.com/read/28841387/efficacy-and-safety-outcomes-in-patients-with-advanced-melanoma-who-discontinued-treatment-with-nivolumab-and-ipilimumab-because-of-adverse-events-a-pooled-analysis-of-randomized-phase-ii-and-iii-trials
#5
Dirk Schadendorf, Jedd D Wolchok, F Stephen Hodi, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean-Jacques Grob, C Lance Cowey, Christopher D Lao, Jason Chesney, Caroline Robert, Kenneth Grossmann, David McDermott, Dana Walker, Rafia Bhore, James Larkin, Michael A Postow
Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409)...
August 25, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28817755/measuring-toxic-effects-and-time-to-treatment-failure-for-nivolumab-plus-ipilimumab-in-melanoma
#6
Alexander N Shoushtari, Claire F Friedman, Pedram Navid-Azarbaijani, Michael A Postow, Margaret K Callahan, Parisa Momtaz, Katherine S Panageas, Jedd D Wolchok, Paul B Chapman
Importance: Nivolumab plus ipilimumab (nivo + ipi) is a standard treatment of advanced melanoma. Two randomized trials describe high objective response rates by Response Evaluation Criteria in Solid Tumors. The trials assessed toxic effects using the Common Terminology Criteria for Adverse Events (CTCAE), which may underestimate incidence of clinically significant immune-related adverse events (AEs). Objective: To describe detailed toxic effects and time to treatment failure of patients with melanoma treated with nivo + ipi in a prospective cohort...
August 17, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28763795/intratumoral-delivery-of-inactivated-modified-vaccinia-virus-ankara-imva-induces-systemic-antitumor-immunity-via-sting-and-batf3-dependent-dendritic-cells
#7
Peihong Dai, Weiyi Wang, Ning Yang, Cristian Serna-Tamayo, Jacob M Ricca, Dmitriy Zamarin, Stewart Shuman, Taha Merghoub, Jedd D Wolchok, Liang Deng
Advanced cancers remain a therapeutic challenge despite recent progress in targeted therapy and immunotherapy. Novel approaches are needed to alter the tumor immunosuppressive microenvironment and to facilitate the recognition of tumor antigens that leads to antitumor immunity. Poxviruses, such as modified vaccinia virus Ankara (MVA), have potential as immunotherapeutic agents. We show that infection of conventional dendritic cells (DCs) with heat- or ultraviolet-inactivated MVA leads to higher levels of interferon induction than MVA alone through the cGAS (cyclic guanosine monophosphate-adenosine monophosphate synthase)-STING cytosolic DNA-sensing pathway...
May 19, 2017: Science Immunology
https://www.readbyqxmd.com/read/28662232/nivolumab-for-patients-with-advanced-melanoma-treated-beyond-progression-analysis-of-2-phase-3-clinical-trials
#8
Georgina V Long, Jeffrey S Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Ivan Márquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F Stephen Hodi, Jedd D Wolchok
Importance: Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression. Objective: To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression...
June 29, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28651159/health-related-quality-of-life-results-from-the-phase-iii-checkmate-067-study
#9
RANDOMIZED CONTROLLED TRIAL
Dirk Schadendorf, James Larkin, Jedd Wolchok, F Stephen Hodi, Vanna Chiarion-Sileni, Rene Gonzalez, Piotr Rutkowski, Jean-Jacques Grob, C Lance Cowey, Christopher Lao, John Wagstaff, Margaret K Callahan, Michael A Postow, Michael Smylie, Pier Francesco Ferrucci, Reinhard Dummer, Andrew Hill, Fiona Taylor, Javier Sabater, Dana Walker, Srividya Kotapati, Amy Abernethy, Georgina V Long
BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL)...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28575677/curbing-tregs-lack-of-enthusiasm
#10
COMMENT
Taha Merghoub, Jedd D Wolchok
In this issue, Overacre-Delgoffe et al. show that interferon gamma production by a subset of regulatory T cells in the tumor microenvironment triggers Treg instability locally and restores anti-tumor immunity.
June 1, 2017: Cell
https://www.readbyqxmd.com/read/28514453/chromatin-states-define-tumour-specific-t-cell-dysfunction-and-reprogramming
#11
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 25, 2017: Nature
https://www.readbyqxmd.com/read/28506536/checkpoint-inhibition-and-melanoma-considerations-in-treating-the-older-adult
#12
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...
July 2017: Journal of Geriatric Oncology
https://www.readbyqxmd.com/read/28397821/t-cell-invigoration-to-tumour-burden-ratio-associated-with-anti-pd-1-response
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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