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pd-1 and cancer

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https://www.readbyqxmd.com/read/28821192/could-the-pd-1-pathway-be-a-potential-target-for-treating-small-intestinal-adenocarcinoma
#1
Ramya Thota, Raul S Gonzalez, Jordan Berlin, Dana B Cardin, Chanjuan Shi
Objectives: The programmed death 1 (PD-1) pathway is upregulated in the immune microenvironment of many cancers. In this study, we examined the PD-1 pathway and the immune microenvironment of small intestinal adenocarcinomas by immunohistochemistry. Methods: From our department pathology archives we identified 42 small intestinal adenocarcinomas from between 2000 and 2015, with blocks available for IHC studies. Tumors were immunohistochemically stained for CD3, CD4, CD8, CD20, PD-1, and programmed death ligand 1 (PD-L1) expression...
September 1, 2017: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/28819856/fiber-optic-array-scanning-technology-fast-for-detection-and-molecular-characterization-of-circulating-tumor-cells
#2
Zheng Ao, Xiaohe Liu
Circulating tumor cell (CTC) as an important component in "liquid biopsy" holds crucial clinical relevance in cancer prognosis, treatment efficiency evaluation, prediction and potentially early detection. Here, we present a Fiber-optic Array Scanning Technology (FAST) that enables antigen-agnostic, size-agnostic detection of CTC. By immunofluorescence staining detection of a combination of a panel of markers, FAST technology can be applied to detect rare CTC in non-small cell lung cancer (NSCLC) setting with high sensitivity and specificity...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28819833/-lymphocytic-myocarditis-in-a%C3%A2-patient-with-metastatic-clear-cell-renal-cell-carcinoma-treated-with-nivolumab
#3
R Sauer, P Kiewe, M Desole, M Schuler, F Theissig, A Roth, T Mairinger
Immune checkpoint inhibitors against the PD-1 protein offer a new therapy option for many solid cancers. We report a patient with metastatic renal cell cancer treated with Nivolumab. As a rare immune-mediated adverse event, we describe a fatal lymphocytic myocarditis two weeks after starting immune therapy. The cause of death was first diagnosed at autopsy. This case report underlines the importance and need of clinical autopsies as an instrument of quality assurance and detection of rare therapy-induced adverse effects...
August 17, 2017: Der Pathologe
https://www.readbyqxmd.com/read/28819582/relationship-of-metabolic-alterations-and-pd-l1-expression-in-cisplatin-resistant-lung-cancer
#4
M Wangpaichitr, H Kandemir, Y Y Li, C Wu, Djm Nguyen, L G Feun, M T Kuo, N Savaraj
Despite numerous reports on immune checkpoint inhibitor for the treatment of non-small cell lung cancer (NSCLC), the response rate remains low but durable. Thus cisplatin still plays a major role in the treatment of NSCLC. While there are many mechanisms involved in cisplatin resistance, alteration in metabolic phenotypes with elevated levels of reactive oxygen species (ROS) are found in several cisplatin resistant tumors. These resistant cells become more reliant on mitochondria oxidative metabolism instead of glucose...
April 28, 2017: Cell & Developmental Biology
https://www.readbyqxmd.com/read/28819402/pd-l1-expression-is-associated-with-foxp3-regulatory-t-cell-infiltration-of-soft-tissue-sarcoma-and-poor-patient-prognosis
#5
Yi Que, Wei Xiao, Yuan-Xiang Guan, Yao Liang, Shu-Mei Yan, Huo-Ying Chen, Qiao-Qiao Li, Bu-Shu Xu, Zhi-Wei Zhou, Xing Zhang
Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T-cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown. Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28819064/the-tumor-microenvironment-regulates-sensitivity-of-murine-lung-tumors-to-pd-1-pdl1-antibody-blockade
#6
Howard Y Li, Maria V McSharry, Bonnie Bullock, Teresa T Nguyen, Jeff Kwak, Joanna M Poczobutt, Trisha R Sippel, Lynn E Heasley, Mary C Weiser-Evans, Eric T Clambey, Raphael A Nemenoff
Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate pre-clinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in--- syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined...
August 17, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28819027/combination-therapy-with-bispecific-antibodies-and-pd-1-blockade-enhances-the-antitumor-potency-of-t-cells
#7
Chien-Hsing Chang, Yang Wang, Rongxiu Li, Diane L Rossi, Donglin Liu, Edmund A Rossi, Thomas M Cardillo, David M Goldenberg
The DOCK-AND-LOCK (DNL®) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL® to generate a novel class of trivalent bispecific antibodies (bsAbs), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. Here we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively...
August 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28818609/multicenter-comparison-of-22c3-pharmdx-agilent-and-sp263-ventana-assays-to-test-pd-l1-expression-for-nsclc-patients-to-be-treated-with-immune-checkpoint-inhibitors
#8
Antonio Marchetti, Massimo Barberis, Renato Franco, Graziano De Luca, Maria Vittoria Pace, Stefania Staibano, Marco Volante, Fiamma Buttitta, Elena Guerini-Rocco, Luisella Righi, Tommaso D'antuono, Giorgio V Scagliotti, Carmine Pinto, Gaetano De Rosa, Mauro Papotti
INTRODUCTION: Among the several agents targeting the programmed cell death 1 (PD-1) pathway, pembrolizumab is currently the only one approved for the treatment of non-small cell lung cancer patients in association with a companion diagnostic assay, the anti-programmed cell death ligand 1 (PD-L1) immunohistochemical (IHC) 22C3 PharmDx (Agilent) using the Dako Autostainer. However, the Dako platform is not present in each pathology department and this technical limitation is a major problem for the diffusion of the PD-L1 IHC predictive test for pembrolizumab...
August 14, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28818454/the-anti-tumor-effect-of-intravesical-administration-of-normal-urothelial-cells-on-bladder-cancer
#9
Chi-Ping Huang, Chi-Cheng Chen, Chih-Rong Shyr
BACKGROUND AIMS: Urothelial bladder cancer (UBC) is the second most common cancer of the genitourinary tract and for advanced forms of the disease it has a high mortality rate. There are no approved new molecularly targeted agents or chemotherapeutics for advanced UBC beyond cisplatin-based chemotherapy except the recently approved anti-programmed death ligand 1 (anti-PD-1/PD-L1) antibody. With complex genetic and epigenetic alterations in tumors, despite several druggable targets identified, to cure UBC is still a challenging unmet medical need...
August 14, 2017: Cytotherapy
https://www.readbyqxmd.com/read/28818019/pembrolizumab-in-the-treatment-of-metastatic-non-small-cell-lung-cancer-a-review-of-current-evidence
#10
Karim Rihawi, Francesco Gelsomino, Francesca Sperandi, Barbara Melotti, Michelangelo Fiorentino, Laura Casolari, Andrea Ardizzoni
Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors...
August 1, 2017: Therapeutic Advances in Respiratory Disease
https://www.readbyqxmd.com/read/28817755/measuring-toxic-effects-and-time-to-treatment-failure-for-nivolumab-plus-ipilimumab-in-melanoma
#11
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/28815913/metastatic-triple-negative-breast-cancer-optimizing-treatment-options-new-and-emerging-targeted-therapies
#12
REVIEW
Parham Khosravi-Shahi, Luis Cabezón-Gutiérrez, Sara Custodio-Cabello
Triple negative breast cancer (TNBC) is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. It also has a distinct epidemiology. TNBCs are frequently of high histologic grade, typically more aggressive and difficult to treat than hormone receptor-positive tumors, and they are associated with a higher risk of early relapse with visceral metastasis after surgery, chemotherapy and/or radiotherapy. The lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression precludes the use of targeted therapies in advanced stages, and the only approved systemic treatment option is chemotherapy with or without bevacizumab...
August 16, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28815334/clinical-characteristics-of-patient-selection-and-imaging-predictors-of-outcome-in-solid-tumors-treated-with-checkpoint-inhibitors
#13
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/28813417/cmtm6-maintains-the-expression-of-pd-l1-and-regulates-anti-tumour-immunity
#14
Marian L Burr, Christina E Sparbier, Yih-Chih Chan, James C Williamson, Katherine Woods, Paul A Beavis, Enid Y N Lam, Melissa A Henderson, Charles C Bell, Sabine Stolzenburg, Omer Gilan, Stuart Bloor, Tahereh Noori, David W Morgens, Michael C Bassik, Paul J Neeson, Andreas Behren, Phillip K Darcy, Sarah-Jane Dawson, Ilia Voskoboinik, Joseph A Trapani, Jonathan Cebon, Paul J Lehner, Mark A Dawson
Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813410/identification-of-cmtm6-and-cmtm4-as-pd-l1-protein-regulators
#15
Riccardo Mezzadra, Chong Sun, Lucas T Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Meike E W Logtenberg, Maarten Slagter, Elisa A Rozeman, Ingrid Hofland, Annegien Broeks, Hugo M Horlings, Lodewyk F A Wessels, Christian U Blank, Yanling Xiao, Albert J R Heck, Jannie Borst, Thijn R Brummelkamp, Ton N M Schumacher
The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein...
August 16, 2017: Nature
https://www.readbyqxmd.com/read/28813164/pembrolizumab-in-patients-with-extensive-stage-small-cell-lung-cancer-results-from-the-phase-ib-keynote-028-study
#16
Patrick A Ott, Elena Elez, Sandrine Hiret, Dong-Wan Kim, Anne Morosky, Sanatan Saraf, Bilal Piperdi, Janice M Mehnert
Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry...
August 16, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28812434/-pemetrexed-sildenafil-via-autophagy-dependent-hdac-down-regulation-enhances-the-immunotherapy-response-of-nsclc-cells
#17
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of Class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment...
August 16, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28811974/ex-vivo-assessment-of-drug-response-on-breast-cancer-primary-tissue-with-preserved-microenvironments
#18
Manuele G Muraro, Simone Muenst, Valentina Mele, Luca Quagliata, Giandomenica Iezzi, Alexandar Tzankov, Walter P Weber, Giulio C Spagnoli, Savas D Soysal
Interaction between cancerous, non-transformed cells, and non-cellular components within the tumor microenvironment plays a key role in response to treatment. However, short-term culture or xenotransplantation of cancer specimens in immunodeficient animals results in dramatic modifications of the tumor microenvironment, thus preventing reliable assessment of compounds or biologicals of potential therapeutic relevance. We used a perfusion-based bioreactor developed for tissue engineering purposes to successfully maintain the tumor microenvironment of freshly excised breast cancer tissue obtained from 27 breast cancer patients and used this platform to test the therapeutic effect of antiestrogens as well as checkpoint-inhibitors on the cancer cells...
2017: Oncoimmunology
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
#19
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/28811967/il-18-receptor-marks-functional-cd8-t-cells-in-non-small-cell-lung-cancer
#20
Eleonora Timperi, Chiara Focaccetti, Daniela Gallerano, Mariangela Panetta, Sheila Spada, Enzo Gallo, Paolo Visca, Federico Venuta, Daniele Diso, Arsela Prelaj, Flavia Longo, Francesco Facciolo, Paola Nisticò, Vincenzo Barnaba
IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC)...
2017: Oncoimmunology
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