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Melanoma pd-1

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https://www.readbyqxmd.com/read/28822576/pembrolizumab-versus-ipilimumab-for-advanced-melanoma-final-overall-survival-results-of-a-multicentre-randomised-open-label-phase-3-study-keynote-006
#1
Jacob Schachter, Antoni Ribas, Georgina V Long, Ana Arance, Jean-Jacques Grob, Laurent Mortier, Adil Daud, Matteo S Carlino, Catriona McNeil, Michal Lotem, James Larkin, Paul Lorigan, Bart Neyns, Christian Blank, Teresa M Petrella, Omid Hamid, Honghong Zhou, Scot Ebbinghaus, Nageatte Ibrahim, Caroline Robert
BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA)...
August 16, 2017: Lancet
https://www.readbyqxmd.com/read/28820000/novel-combination-strategies-for-enhancing-efficacy-of-immune-checkpoint-inhibitors-in-the-treatment-of-metastatic-solid-malignancies
#2
Michael J Flynn, James M G Larkin
Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients. Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness...
August 18, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28817755/measuring-toxic-effects-and-time-to-treatment-failure-for-nivolumab-plus-ipilimumab-in-melanoma
#3
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/28815334/clinical-characteristics-of-patient-selection-and-imaging-predictors-of-outcome-in-solid-tumors-treated-with-checkpoint-inhibitors
#4
REVIEW
Sabrina Rossi, Luca Toschi, Angelo Castello, Fabio Grizzi, Luigi Mansi, Egesta Lopci
The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types...
August 16, 2017: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/28815046/response-to-single-agent-pd-1-inhibitor-after-progression-on-previous-pd-1-pd-l1-inhibitors-a-case-series
#5
Dylan J Martini, Aly-Khan A Lalani, Dominick Bossé, John A Steinharter, Lauren C Harshman, F Stephen Hodi, Patrick A Ott, Toni K Choueiri
BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28811971/preclinical-immunopet-ct-imaging-using-zr-89-labeled-anti-pd-l1-monoclonal-antibody-for-assessing-radiation-induced-pd-l1-upregulation-in-head-and-neck-cancer-and-melanoma
#6
Masahiro Kikuchi, David A Clump, Raghvendra M Srivastava, Lingyi Sun, Dexing Zeng, Julio A Diaz-Perez, Carolyn J Anderson, W Barry Edwards, Robert L Ferris
Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD-L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28807048/response-to-single-agent-pd-1-inhibitor-after-progression-on-previous-pd-1-pd-l1-inhibitors-a-case-series
#7
Dylan J Martini, Aly-Khan A Lalani, Dominick Bossé, John A Steinharter, Lauren C Harshman, F Stephen Hodi, Patrick A Ott, Toni K Choueiri
BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28803728/distinct-cellular-mechanisms-underlie-anti-ctla-4-and-anti-pd-1-checkpoint-blockade
#8
Spencer C Wei, Jacob H Levine, Alexandria P Cogdill, Yang Zhao, Nana-Ama A S Anang, Miles C Andrews, Padmanee Sharma, Jing Wang, Jennifer A Wargo, Dana Pe'er, James P Allison
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28799876/melanoma-brain-metastasis-the-impact-of-stereotactic-radiosurgery-braf-mutational-status-and-targeted-and-or-immune-based-therapies-on-treatment-outcome
#9
Rupesh Kotecha, Jacob A Miller, Vyshak A Venur, Alireza M Mohammadi, Samuel T Chao, John H Suh, Gene H Barnett, Erin S Murphy, Pauline Funchain, Jennifer S Yu, Michael A Vogelbaum, Lilyana Angelov, Manmeet S Ahluwalia
OBJECTIVE The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM). METHODS A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAF (mut) and 43 had BRAF wild-type ( BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk...
August 11, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28789707/checkpoint-inhibitors-in-melanoma-and-early-phase-development-in-solid-tumors-what-s-the-future
#10
EDITORIAL
Paolo A Ascierto, Grant A McArthur
Anti-programmed death (PD)-1 and PD-ligand (L)-1 checkpoint inhibitors have revolutionized the therapy of several cancers. Immunotherapy of cancer can offer long-term durable benefit to patients, is active regardless of tumour histology, has a unique immune-related safety profile, and can be used in combination with other cancer treatments. In addition, recent research has shown that immune-based therapy can be used as adjuvant therapy, that outcomes may be influenced by dose, and that clinical activity is observed in patients with brain metastases...
August 8, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28776578/negative-immune-checkpoint-regulation-by-vista-a-mechanism-of-acquired-resistance-to-anti-pd-1-therapy-in-metastatic-melanoma-patients
#11
Hojabr Kakavand, Louise A Jackett, Alexander M Menzies, Tuba N Gide, Matteo S Carlino, Robyn P M Saw, John F Thompson, James S Wilmott, Georgina V Long, Richard A Scolyer
Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22)...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28775208/a-multikinase-and-dna-pk-inhibitor-combination-immunomodulates-melanomas-suppresses-tumor-progression-and-enhances-immunotherapies
#12
Alexander K Tsai, Asra Y Khan, Christina E Worgo, Lucy L Wang, Yuanyuan Liang, Eduardo Davila
Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas...
August 3, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28761743/checkpoint-inhibitors-in-the-treatment-of-urological-malignancies
#13
REVIEW
Lazar S Popovic, Gorana Matovina-Brko, Maja Popovic
Checkpoint inhibitors are monoclonal antibodies attach to several different receptors on T-cells or tumour cells expressing receptors for cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1) and their ligand (PD-L1). Since 2010, numerous trials on different tumour types have been conducted, which was resulted in these drugs being approved for the treatment of melanoma, lung cancer, Hodgkin's lymphoma and head and neck cancers. Urological cancers, especially urothelial and renal-cell carcinomas, are immunogenic tumours...
2017: ESMO Open
https://www.readbyqxmd.com/read/28760910/epacadostat-shows-value-in-two-scchn-trials
#14
(no author information available yet)
In the ECHO-202/KEYNOTE-037 and ECHO-204 trials reported at the 2017 Annual Meeting of the American Society of Clinical Oncology, patients with squamous cell carcinoma of the head and neck responded well to the combinations of epacadostat plus pembrolizumab and epacadostat plus nivolumab. An IDO1 inhibitor, epacadostat also demonstrated promising activity in combination with the PD-1 checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer...
July 31, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28756306/atypical-responses-in-patients-with-advanced-melanoma-lung-cancer-renal-cell-carcinoma-and-other-solid-tumors-treated-with-anti-pd-1-drugs-a-systematic-review
#15
REVIEW
Paola Queirolo, Francesco Spagnolo
Anti-programmed death receptor 1 (PD-1) drugs nivolumab and pembrolizumab were recently approved for the treatment of advanced melanoma and other solid tumors. Atypical patterns of response (i.e. tumor shrinkage or stabilization after initial progression) were observed in about 10% of metastatic melanoma patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drug ipilimumab and were associated with improved survival; however, the rate of atypical response patterns to anti-PD-1 therapy is not clear...
July 19, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28756137/survival-of-patients-with-advanced-metastatic-melanoma-the-impact-of-novel-therapies-update-2017
#16
REVIEW
Selma Ugurel, Joachim Röhmel, Paolo A Ascierto, Keith T Flaherty, Jean Jacques Grob, Axel Hauschild, James Larkin, Georgina V Long, Paul Lorigan, Grant A McArthur, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Claus Garbe
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma...
July 27, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28754882/a-regulatory-role-for-the-co-chaperone-fkbp51s-in-pd-l1-expression-in-glioma
#17
Paolo D'Arrigo, Michele Russo, Anna Rea, Martina Tufano, Elia Guadagno, Maria Laura Del Basso De Caro, Roberto Pacelli, Felix Hausch, Stefania Staibano, Gennaro Ilardi, Silvia Parisi, Maria Fiammetta Romano, Simona Romano
BACKGROUND: FKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour. METHODS: We used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1...
July 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28750150/are-checkpoint-inhibitors-a-valuable-option-for-metastatic-or-unresectable-vulvar-and-vaginal-melanomas
#18
G Quéreux, S Wylomanski, R Bouquin, M Saint-Jean, L Peuvrel, A C Knol, M Hanf, B Dréno
Immune checkpoint inhibitors might be therapeutic options for unresectable or metastatic melanomas of the vulva and vagina but data available in the literature in these melanomas are very limited (1)(2)(3)(4) . The aim of this retrospective study was to investigate the effect of anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed death 1 (PD-1) antibodies in patients treated in our Skin Cancer Department for unresectable or metastatic vulvar or vaginal melanoma since 2013. This article is protected by copyright...
July 27, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28746871/the-histone-methyltransferase-ezh2-controls-mechanisms-of-adaptive-resistance-to-tumor-immunotherapy
#19
Daniel Zingg, Natalia Arenas-Ramirez, Dilara Sahin, Rodney A Rosalia, Ana T Antunes, Jessica Haeusel, Lukas Sommer, Onur Boyman
Immunotherapy and particularly immune checkpoint inhibitors have resulted in remarkable clinical responses in patients with immunogenic tumors, although most cancers develop resistance to immunotherapy. The molecular mechanisms of tumor resistance to immunotherapy remain poorly understood. We now show that induction of the histone methyltransferase Ezh2 controls several tumor cell-intrinsic and extrinsic resistance mechanisms. Notably, T cell infiltration selectively correlated with high EZH2-PRC2 complex activity in human skin cutaneous melanoma...
July 25, 2017: Cell Reports
https://www.readbyqxmd.com/read/28743833/therapeutic-vaccine-to-cure-large-mouse-hepatocellular-carcinomas
#20
Zhen Han, De Yang, Anna Trivett, Joost J Oppenheim
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Here we report the development of a therapeutic vaccination regimen (shortened as 'TheraVac') consisting of intratumoral delivery of high-mobility group nucleosome-binding protein 1 (HMGN1), R848/resiquimod, and one of the checkpoint inhibitors (e.g. anti-CTLA4, anti-PD-L1, or low dose of Cytoxan). C57BL/6 mice harboring large (approximately 1 cm in diameter) established subcutaneous Hepa1-6 hepatomas were cured by intratumoral injections of TheraVac and became tumor-free long-term survivors...
July 18, 2017: Oncotarget
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