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PD-1 PD-L1

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https://www.readbyqxmd.com/read/28432789/probing-protein-flexibility-reveals-a-mechanism-for-selective-promiscuity
#1
Nicolas A Pabon, Carlos J Camacho
Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anti-cancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity...
April 22, 2017: ELife
https://www.readbyqxmd.com/read/28432648/rationale-for-new-checkpoint-inhibitor-combinations-in-melanoma-therapy
#2
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/28432616/prognostic-impact-of-pd-1-and-its-ligands-in-renal-cell-carcinoma
#3
REVIEW
Franziska Erlmeier, Wilko Weichert, Andres Jan Schrader, Michael Autenrieth, Arndt Hartmann, Sandra Steffens, Philipp Ivanyi
Programmed death-1 receptor (PD-1) and programmed death-1 receptor-ligand (PD-L1) have been suggested to play a role as prognostic markers in clear cell renal cell carcinoma (ccRCC). The association between PD-L1 and prognosis seems to be more robust than for PD-1. Further, preliminary analyses suggest that neither PD-1 nor its ligands play a role as prognostic markers in non-clear cell RCC, while the prognostic role of PD-L2 in ccRCC as well as in non-clear cell RCC remains unclear.
June 2017: Medical Oncology
https://www.readbyqxmd.com/read/28431010/clinical-trial-of-the-anti-pd-l1-antibody-bms-936559-in-hiv-1-infected-participants-on-suppressive-antiretroviral-therapy
#4
Cynthia L Gay, Ronald J Bosch, Justin Ritz, Jason M Hataye, Evgenia Aga, Randall L Tressler, Stephen W Mason, Carey K Hwang, Dennis M Grasela, Neelanjana Ray, Josh C Cyktor, John M Coffin, Edward P Acosta, Richard A Koup, John W Mellors, Joseph J Eron
Background.: Reversing immune exhaustion with an anti-PD-L1 antibody may improve HIV-1-specific immunity and increase clearance of HIV-1 expressing cells. Methods.: Phase I, randomized, double-blind, placebo-controlled dose-escalating study of BMS-936559including HIV-1-infected adults ≥18 to ≤70 years on suppressive antiretroviral therapy with CD4+ counts ≥350 cells/μL and detectable plasma HIV-1 RNA by single copy assay. Data on single infusions of BMS-936559 (0...
April 18, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28430664/identification-of-a-novel-pd-l1-positive-solid-tumor-transplantable-in-hla-a-0201-drb1-0101-transgenic-mice
#5
Laurie Rangan, Jeanne Galaine, Romain Boidot, Mohamad Hamieh, Magalie Dosset, Julie Francoual, Laurent Beziaud, Jean-René Pallandre, Elodie Lauret Marie Joseph, Afag Asgarova, Christophe Borg, Talal Al Saati, Yann Godet, Jean Baptiste Latouche, Séverine Valmary-Degano, Olivier Adotévi
HLA-A*0201/DRB1*0101 transgenic mice (A2/DR1 mice) have been developed to study the immunogenicity of tumor antigen-derived T cell epitopes. To extend the use and application of this mouse model in the field of antitumor immunotherapy, we described a tumor cell line generated from a naturally occurring tumor in A2/DR1 mouse named SARC-L1. Histological and genes signature analysis supported the sarcoma origin of this cell line. While SARC-L1 tumor cells lack HLA-DRB1*0101 expression, a very low expression of HLA-A*0201 molecules was found on these cells...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430626/expression-of-pd-l1-and-prognosis-in-breast-cancer-a-meta-analysis
#6
Minghui Zhang, Houbin Sun, Shu Zhao, Yan Wang, Haihong Pu, Yan Wang, Qingyuan Zhang
The associations between programmed cell death ligand 1 (PD-L1) and the prognosis of various cancers have always been a research topic of considerable interest. However, the prognostic value of PD-L1 in breast cancer patients remains a controversial subject. We aimed to assess the association between PD-L1 protein expression and clinicopathological features and the impact of this relationship on breast cancer survival. We performed a systematic search of the PubMed, EMBASE, and Cochrane Library databases to determine the correlations among PD-L1 expression, clinicopathological features and overall survival (OS)...
February 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28428947/update-on-programmed-death-1-and-programmed-death-ligand-1-inhibition-in-the-treatment-of-advanced-or-metastatic-non-small-cell-lung-cancer
#7
REVIEW
Marco A J Iafolla, Rosalyn A Juergens
PURPOSE: Non-small-cell lung cancer (NSCLC) has a large worldwide prevalence with a high mortality rate. Chemotherapy has offered modest improvements in survival over the past two decades. Immune checkpoint modulation with programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition has shown the promise of changing the future landscape of cancer therapy. This update reviews recent advances in the treatment of NSCLC with immune checkpoint modulation. METHODS: Publications and proceedings were identified from searching PubMed and proceedings from the annual meetings of the American Society of Clinical Oncology, European Society for Medical Oncology, and European Lung Cancer Conference...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28428785/interferon-gamma-induces-changes-in-natural-killer-nk-cell-ligand-expression-and-alters-nk-cell-mediated-lysis-of-pediatric-cancer-cell-lines
#8
Arianexys Aquino-López, Vladimir V Senyukov, Zlatko Vlasic, Eugenie S Kleinerman, Dean A Lee
Natural killer (NK) cells have therapeutic potential for cancer due to their capacity for targeting tumor cells without prior sensitization. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion that secret 20 times the amount of interferon gamma (IFNγ) than resting NK cells. IFNγ can upregulate major histocompatibility complex (MHC)-class I, an inhibitory ligand for NK cells, but can also upregulate intercellular adhesion molecule 1 (ICAM-1) which promotes NK:target cell interaction for an efficient lysis...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28428193/pd-l1-expression-in-melanoma-a-quantitative-immunohistochemical-antibody-comparison
#9
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/28427861/divergent-function-of-programmed-death-ligand-1-in-donor-tissue-versus-recipient-immune-system-in-a-murine-model-of-bronchiolitis-obliterans
#10
Katharina Schütte-Nütgen, Olaf Boenisch, Hakima Harrach, Alicia Casey, Indira Guleria, Nader Najafian, Mohamed H Sayegh, Craig J Gerard, Meera Subramaniam
Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue...
April 17, 2017: American Journal of Pathology
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
#11
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/28424325/fda-approval-summary-atezolizumab-for-the-treatment-of-patients-with-progressive-advanced-urothelial-carcinoma-after-platinum-containing-chemotherapy
#12
Yang-Min Ning, Daniel Suzman, V Ellen Maher, Lijun Zhang, Shenghui Tang, Tiffany Ricks, Todd Palmby, Wentao Fu, Qi Liu, Kirsten B Goldberg, Geoffrey Kim, Richard Pazdur
Until recently in the United States, no products were approved for second-line treatment of advanced urothelial carcinoma. On May 18, 2016, the U.S. Food and Drug Administration approved atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Atezolizumab is a programmed death-ligand 1 (PD-L1) blocking antibody and represents the first approved product directed against PD-L1...
April 19, 2017: Oncologist
https://www.readbyqxmd.com/read/28424162/pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-with-richter-s-transformation-and-relapsed-cll
#13
Wei Ding, Betsy R LaPlant, Timothy G Call, Sameer A Parikh, Jose F Leis, Rong He, Tait D Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas M Habermann, Thomas E Witzig, Gregory A Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J Conte, Deborah A Bowen, Casey N Aitken, Daniel L Van Dyke, Patricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R Secreto, Shulan Tian, Esteban Braggio, Linda E Wellik, Ivana Micallef, David S Viswanatha, Huihuang Yan, Asher A Chanan-Khan, Neil E Kay, Haidong Dong, Stephen M Ansell
CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study MC1485 (NCT02332980) was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled and 60% received prior ibrutinib...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28423587/the-correlation-between-programmed-death-ligand-1-expression-and-driver-gene-mutations-in-nsclc
#14
Haitao Yang, Huijuan Chen, Shuimei Luo, Lina Li, Sijing Zhou, Ruifen Shen, Heng Lin, Xianhe Xie
OBJECTIVES: This study aimed to evaluate the correlation between positive PD-L1 expression and driver gene mutations in NSCLC and to seek preliminary evidence in favor of the strategy of PD-L1 inhibitors plus targeted agents. RESULTS: The overall analyses revealed that positive PD-L1 expression had a significant relationship with KRAS status (RR = 1.26; 95% CI, 1.06-1.50, P = 0.010), but no correlation with clinical characteristics (gender, smoking status, histological types), driver gene status (EGFR, ALK) and overall survival (OS): male versus female (RR = 1...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423552/enhanced-antitumor-effects-by-combining-an-il-12-anti-dna-fusion-protein-with-avelumab-an-anti-pd-l1-antibody
#15
Jonathan K Fallon, Amanda J Vandeveer, Jeffrey Schlom, John W Greiner
The combined therapeutic potential of an immunocytokine designed to deliver IL-12 to the necrotic regions of solid tumors with an anti-PD-L1 antibody that disrupts the immunosuppressive PD-1/PD-L1 axis yielded a combinatorial benefit in multiple murine tumor models. The murine version of the immunocytokine, NHS-muIL12, consists of an antibody (NHS76) recognizing DNA/DNA-histone complexes, fused with two molecules of murine IL-12 (NHS-muIL12). By its recognition of exposed DNA, NHS-muIL12 targets IL-12 to the necrotic portions of tumors; it has a longer plasma half-life and better antitumor efficacy against murine tumors than recombinant murine IL-12...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423520/prognostic-role-of-programmed-death-ligand-1-pd-l1-expressing-tumor-infiltrating-lymphocytes-in-testicular-germ-cell-tumors
#16
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/28423034/elevated-frequencies-of-cd8-t-cells-expressing-pd-1-ctla-4-and-tim-3-within-tumour-from-perineural-squamous-cell-carcinoma-patients
#17
Richard Linedale, Campbell Schmidt, Brigid T King, Annabelle G Ganko, Fiona Simpson, Benedict J Panizza, Graham R Leggatt
Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas...
2017: PloS One
https://www.readbyqxmd.com/read/28421161/incidence-of-immune-related-adverse-events-with-program-death-receptor-1-and-program-death-receptor-1-ligand-directed-therapies-in-genitourinary-cancers
#18
REVIEW
Benjamin L Maughan, Erin Bailey, David M Gill, Neeraj Agarwal
Program death receptor-1 (PD-1) and program death receptor-1 ligand (PD-L1) inhibitors are increasingly being used in the clinic to treat a growing number of malignancies, including many genitourinary (GU) malignancies. These immune-based therapies have demonstrated a distinct toxicity profile compared to traditional chemotherapy and the targeted therapies directed at the vascular endothelial growth factor pathway or the mammalian target of rapamycin pathway. Autoimmune toxicity targeting the skin, gastrointestinal tract, or the endocrine organs are some of the more common adverse events (AEs) noted with these therapies...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28420726/intra-and-inter-observer-reproducibility-assessment-of-pd-l1-biomarker-in-non-small-cell-lung-cancer-nsclc
#19
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/28420421/analysis-of-100-000-human-cancer-genomes-reveals-the-landscape-of-tumor-mutational-burden
#20
Zachary R Chalmers, Caitlin F Connelly, David Fabrizio, Laurie Gay, Siraj M Ali, Riley Ennis, Alexa Schrock, Brittany Campbell, Adam Shlien, Juliann Chmielecki, Franklin Huang, Yuting He, James Sun, Uri Tabori, Mark Kennedy, Daniel S Lieber, Steven Roels, Jared White, Geoffrey A Otto, Jeffrey S Ross, Levi Garraway, Vincent A Miller, Phillip J Stephens, Garrett M Frampton
BACKGROUND: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. METHODS: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome...
April 19, 2017: Genome Medicine
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