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https://www.readbyqxmd.com/read/28432648/rationale-for-new-checkpoint-inhibitor-combinations-in-melanoma-therapy
#1
Mario Mandalà, Carlo Tondini, Barbara Merelli, Daniela Massi
The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies...
April 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28428193/pd-l1-expression-in-melanoma-a-quantitative-immunohistochemical-antibody-comparison
#2
Joel C Sunshine, Peter Nguyen, Genevieve Kaunitz, Tricia Cottrell, Sneha Berry, Jessica Esandrio, Haiying Xu, Aleksandra Ogurtsova, Karen R Bleich, Toby C Cornish, Evan J Lipson, Robert A Anders, Janis Taube
PD-L1 expression in the pre-treatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.  <br /><br />Experimental Design: PD-L1 immunohistochemistry (IHC) was performed on thirty-four formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3 and SP263 clones.  The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform...
April 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28427522/the-role-of-anti-pd-1-and-anti-pd-l1-agents-in-the-treatment-of-diffuse-large-b-cell-lymphoma-the-future-is-now
#3
REVIEW
Luis Miguel Juárez-Salcedo, Jose Sandoval-Sus, Lubomir Sokol, Julio C Chavez, Samir Dalia
Immune checkpoints inhibitors have been incorporated into standard treatment protocols for advanced solid tumors. The aim of T-cell-based immune therapy in cancer has been to generate durable clinical benefits for patients, paired with enhanced side effect profiles. The beneficial antitumoral activity of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has been thoroughly demonstrated in certain metastatic malignancies (e.g. melanoma, non-small cell lung cancer, renal cell carcinoma); however, the therapeutic role in lymphoid cancers is complex...
May 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28426103/neurotoxicity-from-immune-checkpoint-inhibition-in-the-treatment-of-melanoma-a-single-centre-experience-and-review-of-the-literature
#4
L Spain, G Walls, M Julve, K O'Meara, T Schmid, E Kalaitzaki, S Turajlic, M Gore, J Rees, J Larkin
Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab...
February 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28423520/prognostic-role-of-programmed-death-ligand-1-pd-l1-expressing-tumor-infiltrating-lymphocytes-in-testicular-germ-cell-tumors
#5
Michal Chovanec, Zuzana Cierna, Viera Miskovska, Katarina Machalekova, Daniela Svetlovska, Katarina Kalavska, Katarina Rejlekova, Stanislav Spanik, Karol Kajo, Pavel Babal, Jozef Mardiak, Michal Mego
PURPOSE: Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs. RESULTS: PD-L1 positive TILs were found significantly more often in seminomas (95...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423334/two-strings-in-one-bow-pd-1-negatively-regulates-via-co-receptor-cd28-on-t-cells
#6
Janna Krueger, Christopher E Rudd
The identity of PD-1 dependency on other receptors and signaling has been unclear. In a recent issue of Science, Hui et al. (2017) and Kamphorst et al. (2017) now show that CD28 expression is a target of PD-1-associated phosphatases and is needed for T cell expansion in anti-PD-1 immunotherapy.
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28420726/intra-and-inter-observer-reproducibility-assessment-of-pd-l1-biomarker-in-non-small-cell-lung-cancer-nsclc
#7
Wendy A Cooper, Prudence A Russell, Maya Cherian, Edwina E Duhig, David Godbolt, Peter J Jessup, Christine Khoo, Connull Leslie, Annabelle Mahar, David F Moffat, Vanathi Sivasubramaniam, Céline Faure, Alena Reznichenko, Amanda Grattan, Stephen B Fox
<br />Reliable and reproducible methods for identifying PD-L1 expression on tumor cells are necessary to identify responders to anti-PD-1 therapy. We tested the reproducibility of the assessment of PD-L1 expression in non-small cell lung cancer (NSCLC) tissue samples by pathologists.<br />Experimental Design: <br />NSCLC samples were stained with PD-L1 22C3 pharmDx™ kit using the Dako Autostainer Link 48 Platform. Two sample sets of 60 samples each were designed to assess inter- and intra-observer reproducibility considering 2 cut-points for positivity: 1% or 50% of PD-L1 stained tumor cells...
April 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28419570/oral-lichenoid-reactions-associated-with-anti-pd-1-pd-l1-therapies-clinicopathological-findings
#8
V Sibaud, C Eid, V R Belum, P Combemale, B Barres, L Lamant, L Mourey, C Gomez-Roca, C L Estilo, R Motzer, E Vigarios, Mario E Lacouture
Immune checkpoint inhibitors targeting the programmed cell death receptor-1 (PD-1) or its ligand (PD-L1) show broad activity across different tumor types and currently represent one of the keystones of cancer management. Dermatologic toxicities are one of the most frequent immune-related adverse events (irAEs) induced by these new monoclonal antibodies. Maculopapular rash, pruritus, exacerbation of psoriasis or more specific autoimmune disorders (e.g. vitiligo, alopecia areata, and bullous pemphigoid) are amongst the most commonly reported AEs...
April 17, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28419181/hyperprogression-during-anti-pd-1-pd-l1-therapy-in-patients-with-recurrent-and-or-metastatic-head-and-neck-squamous-cell-carcinoma
#9
E Saâda-Bouzid, C Defaucheux, A Karabajakian, V Palomar Coloma, V Servois, X Paoletti, C Even, J Fayette, J Guigay, D Loirat, F Peyrade, M Alt, J Gal, C Le Tourneau
Background: HASH(0x4326fd8) Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK). Patients and Methods: HASH(0x50f3458) We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers...
April 13, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28418115/aggravation-of-diabetes-and-incompletely-deficient-insulin-secretion-in-a-case-with-type-1-diabetes-resistant-hla-drb1-15-02-treated-with-nivolumab
#10
Kimio Matsumura, Kaoru Nagasawa, Yoichi Oshima, Shouta Kikuno, Kyohei Hayashi, Akihiro Nishimura, Minoru Okubo, Hironori Uruga, Kazuma Kishi, Tetsuro Kobayashi, Yasumichi Mori
Anti-programmed cell death-1 (PD-1) antibody therapy induces various adverse effects especially in endocrine systems. Several cases of acute onset insulin-dependent diabetes after anti-PD-1 antibody therapy have been reported. Many of these cases have a susceptible HLA genotype for type 1 diabetes possibly suggesting that human leukocyte antigen (HLA) might be involved in the onset of diabetes with anti PD-1 therapy. We describe an atypical case of hyperglycemia after anti PD-1 antibody administration. A 68-year-old Japanese man with pancreatic diabetes and steroid diabetes was administered nivolumab three times for chemoresistant adenocarcinoma of the lung...
April 18, 2017: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/28417343/adjuvant-therapy-for-melanoma
#11
REVIEW
Aya Agha, Ahmad A Tarhini
Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs...
May 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28411193/liver-metastasis-and-treatment-outcome-with-anti-pd-1-monoclonal-antibody-in-patients-with-melanoma-and-nsclc
#12
Paul C Tumeh, Matthew D Hellmann, Omid Hamid, Katy K Tsai, Kimberly L Loo, Matthew A Gubens, Michael Rosenblum, Christina L Harview, Janis Taube, Nathan Handley, Neharika Khurana, Adi Nosrati, Matthew F Krummel, Andrew Tucker, Eduardo Sosa, Philip J Sanchez, Nooriel Banayan, Juan Osorio, Dan L Nguyen-Kim, Jeremy Chang, I Peter Shintaku, Peter Boasberg, Emma J Taylor, Pamela N Munster, Alain P Algazi, Bartosz Chmielowski, Reinhard Dummer, Tristan R Grogan, David A Elashoff, Jimmy Hwang, Simone Goldinger, Edward Garon, Robert H Pierce, Adil I Daud
We explored the association between liver metastases, tumor CD8+ T cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the Phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival (PFS); [objective response rate (ORR), 30...
April 14, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28405527/jak-stat-mediated-chronic-inflammation-impairs-cytotoxic-t-lymphocyte-activation-to-decrease-anti-pd-1-immunotherapy-efficacy-in-pancreatic-cancer
#13
Chunwan Lu, Asif Talukder, Natasha M Savage, Nagendra Singh, Kebin Liu
Human pancreatic cancer does not respond to immune check point blockade immunotherapy. One key feature of pancreatic cancer is the association between its progression and chronic inflammation. Emerging evidence supports a key role for the JAK-STAT pathway in pancreatic cancer inflammation. We aimed at testing the hypothesis that sustained JAK-STAT signaling suppresses cytotoxic T lymphocyte (CTL) activation to counteract anti-PD-1 immunotherapy-induced CTL activity in pancreatic cancer. We show that human pancreatic carcinomas express high level of PD-L1 and exhibit low level of CTL infiltration...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28401596/successful-retreatment-with-combined-braf-mek-inhibition-in-metastatic-brafv600-mutated-melanoma
#14
Valerie C Amann, Dorothée Hoffmann, Joanna Mangana, Reinhard Dummer, Simone M Goldinger
BACKGROUND: The combination treatment with BRAF- and MEK-inhibitors is amongst the current standard of care for stage IIIC/IV BRAF-mutated melanoma. However, therapeutic options are limited once patients have progressed upon both targeted and immunotherapy. OBJECTIVE: To investigate whether retreatment with BRAF- and MEK-inhibitor combination is an option for patients with metastatic BRAF-mutated melanoma upon previous progression on kinase inhibitors. METHODS: Two patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF- and MEK-inhibitor combination after progression on targeted therapy and subsequent immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies...
April 12, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28401381/antiangiogenic-therapy-combined-with-immune-checkpoint-blockade-in-renal-cancer
#15
REVIEW
Teele Kuusk, Laurence Albiges, Bernard Escudier, Nikolaos Grivas, John Haanen, Thomas Powles, Axel Bex
Antiangiogenic therapy with vascular endothelial growth factor (VEGF) inhibitors is the current first-line treatment in metastatic renal cell carcinoma (mRCC). Immunotherapy with checkpoint inhibitor has been recently added to the armamentarium of mRCC treatment. These therapies are based on treatment with antibodies that block programmed cell death-1 (PD-1), programmed cell death ligand 1 (PD-L1) pathways, demonstrating impressive response rates and improved survival in several tumour types. So far, nivolumab is the only approved anti-PD-1 monoclonal antibody after VEGF therapy in mRCC...
April 11, 2017: Angiogenesis
https://www.readbyqxmd.com/read/28401366/resistance-to-immunotherapy-clouds-in-a-bright-sky
#16
REVIEW
Gérard Milano
Two major challenges persist for an optimal management of immunotherapy: i) identifying those patients who will benefit from this type of therapy, and ii) determining the biological, cellular and molecular mechanisms that trigger disease progression while on therapy. There is a consensual view in favor of standardizing practices currently used to measure programmed death ligand 1 (PD-L1) expression that relates to innate resistance. The tumor mutation landscape has been widely explored as a potential predictor of treatment efficacy...
April 12, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28400597/indicators-of-responsiveness-to-immune-checkpoint-inhibitors
#17
Bradley D Shields, Fade Mahmoud, Erin M Taylor, Stephanie D Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel G Mackintosh, Ricky D Edmondson, Sara Shalin, Alan J Tackett
Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors (ICI), in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28397821/t-cell-invigoration-to-tumour-burden-ratio-associated-with-anti-pd-1-response
#18
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)...
April 10, 2017: Nature
https://www.readbyqxmd.com/read/28397730/programmed-cell-death-1-programmed-death-ligand-1-pathway-a-new-target-for-sepsis
#19
REVIEW
Qiang Liu, Chun-Sheng Li
OBJECTIVE: Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment...
April 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28396509/clinical-features-of-acquired-resistance-to-anti-pd-1-therapy-in-advanced-melanoma
#20
Daniel Y Wang, Zeynep Eroglu, Alpaslan Ozgun, Paul D Leger, Shilin Zhao, Fei Ye, Jason J Luke, Richard W Joseph, Rizwan Haq, Patrick A Ott, F Stephen Hodi, Jeffrey A Sosman, Douglas B Johnson, Elizabeth I Buchbinder
Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab...
April 10, 2017: Cancer Immunology Research
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