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https://www.readbyqxmd.com/read/28441111/phase-ii-study-of-the-efficacy-and-safety-of-pembrolizumab-for-relapsed-refractory-classic-hodgkin-lymphoma
#1
Robert Chen, Pier Luigi Zinzani, Michelle A Fanale, Philippe Armand, Nathalie A Johnson, Pauline Brice, John Radford, Vincent Ribrag, Daniel Molin, Theodoros P Vassilakopoulos, Akihiro Tomita, Bastian von Tresckow, Margaret A Shipp, Yinghua Zhang, Alejandro D Ricart, Arun Balakumaran, Craig H Moskowitz
Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation...
April 25, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28440953/immunotherapy-with-single-agent-nivolumab-for-advanced-leiomyosarcoma-of-the-uterus-results-of-a-phase-2-study
#2
Eytan Ben-Ami, Constance M Barysauskas, Sarah Solomon, Kadija Tahlil, Rita Malley, Melissa Hohos, Kathleen Polson, Margaret Loucks, Mariano Severgnini, Tara Patel, Amy Cunningham, Scott J Rodig, F Stephen Hodi, Jeffrey A Morgan, Priscilla Merriam, Andrew J Wagner, Geoffrey Shapiro, Suzanne George
BACKGROUND: Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population. METHODS: This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity...
April 25, 2017: Cancer
https://www.readbyqxmd.com/read/28439267/pulmonary-delivery-of-virosome-bound-antigen-enhances-antigen-specific-cd4-t-cell-proliferation-compared-to-liposome-bound-or-soluble-antigen
#3
Rebecca A M Blom, Mario Amacker, R Maarten van Dijk, Christian Moser, Philip A Stumbles, Fabian Blank, Christophe von Garnier
Pulmonary administration of biomimetic nanoparticles loaded with antigen may represent an effective strategy to directly modulate adaptive immune responses in the respiratory tract. Depending on the design, virosomes may not only serve as biomimetic antigen carriers but are also endowed with intrinsic immune-stimulatory properties. We designed fluorescently labeled influenza-derived virosomes and liposome controls coupled to the model antigen ovalbumin to investigate uptake, phenotype changes, and antigen processing by antigen-presenting cells exposed to such particles in different respiratory tract compartments...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28436955/vitamin-a-mediates-conversion-of-monocyte-derived-macrophages-into-tissue-resident-macrophages-during-alternative-activation
#4
Uma Mahesh Gundra, Natasha M Girgis, Michael A Gonzalez, Mei San Tang, Hendrik J P Van Der Zande, Jian-Da Lin, Mireille Ouimet, Lily J Ma, Jordan Poles, Nikollaq Vozhilla, Edward A Fisher, Kathryn J Moore, P'ng Loke
It remains unclear whether activated inflammatory macrophages can adopt features of tissue-resident macrophages, or what mechanisms might mediate such a phenotypic conversion. Here we show that vitamin A is required for the phenotypic conversion of interleukin 4 (IL-4)-activated monocyte-derived F4/80(int)CD206(+)PD-L2(+)MHCII(+) macrophages into macrophages with a tissue-resident F4/80(hi)CD206(-)PD-L2(-)MHCII(-)UCP1(+) phenotype in the peritoneal cavity of mice and during the formation of liver granulomas in mice infected with Schistosoma mansoni...
April 24, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28432789/probing-protein-flexibility-reveals-a-mechanism-for-selective-promiscuity
#5
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/28432616/prognostic-impact-of-pd-1-and-its-ligands-in-renal-cell-carcinoma
#6
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/28416578/quantitative-mass-spectrometry-analysis-of-pd-l1-protein-expression-n-glycosylation-and-expression-stoichiometry-with-pd-1-and-pd-l2-in-human-melanoma
#7
Carlos A Morales-Betanzos, Hyoungjoo Lee, Paula I Gonzalez-Ericsson, Justin M Balko, Douglas B Johnson, Lisa J Zimmerman, Daniel C Liebler
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed a targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody...
April 17, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28408783/prokaryotic-expression-of-the-extracellular-domain-of-porcine-programmed-death-1-pd-1-and-its-ligand-pd-l1-and-identification-of-the-binding-with-peripheral-blood-mononuclear-cells-in-vitro
#8
Yan-Ping Zhu, Feng Yue, Yong He, Peng Li, Yuan Yang, Yu-Ting Han, Yan-Fang Zhang, Guo-Peng Sun, Dong-Guang Guo, Mei Yin, Xuan-Nian Wang
Programmed cell death protein 1 (PD-1), a costimulatory molecule of the CD28 family, has 2 ligands, PD-L1 and PD-L2. Our previous studies showed that the expression of PD-1 and PD-L1 is up-regulated during viral infection in pigs. Extensive studies have shown that blockade of the PD-1/PD-L1 pathways by anti-PD-L1 antibody or soluble PD-1 restores exhausted T-cells in humans and mice. In the present study the extracellular domains of PD-1 and PD-L1 were used to evaluate the binding of PD-1 and PD-L1 with peripheral blood mononuclear cells (PBMCs)...
April 2017: Canadian Journal of Veterinary Research, Revue Canadienne de Recherche Vétérinaire
https://www.readbyqxmd.com/read/28405512/high-expression-of-pd-1-ligands-is-associated-with-kataegis-mutational-signature-and-apobec3-alterations
#9
Amélie Boichard, Igor F Tsigelny, Razelle Kurzrock
Immunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic and phenotypic data related to 8,475 pan-cancer samples available in The Cancer Genome Atlas (TCGA) and conducted a logistic regression analysis based on a large set of variables, such as microsatellite instability (MSI-H), mismatch repair (MMR) alterations, polymerase δ (POLD1) and polymerase ε (POLE) mutations, activation-induced/apolipoprotein-B editing cytidine deaminases (AID/APOBEC) alterations, lymphocyte markers and mutation burden estimates to determine independent factors that associate with PD-1 ligand overexpression...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28402953/mechanisms-of-pd-1-pd-l1-expression-and-prognostic-relevance-in-non-hodgkin-lymphoma-a-summary-of-immunohistochemical-studies
#10
REVIEW
Pauline Gravelle, Barbara Burroni, Sarah Péricart, Cédric Rossi, Christine Bezombes, Marie Tosolini, Diane Damotte, Pierre Brousset, Jean-Jacques Fournié, Camille Laurent
Immune checkpoint blockade therapeutics, notably antibodies targeting the programmed death 1 (PD-1) receptor and its PD-L1 and PD-L2 ligands, are currently revolutionizing the treatment of cancer. For a sizeable fraction of patients with melanoma, lung, kidney and several other solid cancers, monoclonal antibodies that neutralize the interactions of the PD-1/PD-L1 complex allow the reconstitution of long-lasting antitumor immunity. In hematological malignancies this novel therapeutic strategy is far less documented, although promising clinical responses have been seen in refractory and relapsed Hodgkin lymphoma patients...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28393361/immune-checkpoints-and-their-inhibition-in-cancer-and-infectious-diseases
#11
REVIEW
Lydia Dyck, Kingston H G Mills
The development of chronic infections and cancer is facilitated by a variety of immune subversion mechanisms, such as the production of anti-inflammatory cytokines, induction of regulatory T (Treg) cells, and expression of immune checkpoint molecules, including CTLA-4 and PD-1. CTLA-4, expressed on T cells, interacts with CD80/CD86, thereby limiting T-cell activation and leading to anergy. PD-1 is predominantly expressed on T cells and its interaction with PD-L1 and PD-L2 expressed on antigen-presenting cells (APCs) and tumors sends a negative signal to T cells, which can lead to T-cell exhaustion...
April 9, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28356247/pd-1-blockade-with-nivolumab-in-relapsed-refractory-primary-central-nervous-system-and-testicular-lymphoma
#12
Lakshmi Nayak, Fabio M Iwamoto, Ann LaCasce, Srinivasan Mukundan, Margaretha G M Roemer, Bjoern Chapuy, Philippe Armand, Scott J Rodig, Margaret A Shipp
Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare extranodal large B-cell lymphomas with similar genetic signatures. There are no standard of care treatment options for patients with relapsed and refractory PCNSL and PTL, and the overall prognosis is poor. PCNSLs and PTLs exhibit frequent 9p24.1 copy number alterations and infrequent translocations of 9p24.1 and associated increased expression of the programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2...
March 29, 2017: Blood
https://www.readbyqxmd.com/read/28353093/pd-l2-a-prognostic-marker-in-chromophobe-renal-cell-carcinoma
#13
Franziska Erlmeier, Wilko Weichert, Michael Autenrieth, Max Wiedemann, Andres Jan Schrader, Arndt Hartmann, Philipp Ivanyi, Sandra Steffens
In the context of cancer immunotherapy, PD-1 as well as PD-L1 has been widely studied in renal cell carcinoma (RCC). PD-1 and PD-L1 play a significant role as prognostic markers in clear cell renal cell carcinoma. In contrast, little is known about PD-L2 expression patterns in RCC, especially in rarer subtypes. The aim of this study was to evaluate the prevalence, distribution and prognostic impact of PD-L2 expression in chromophobe (ch)RCC. Eighty-one patients who underwent renal surgery due to chRCC were retrospectively evaluated...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28332100/expression-of-programmed-death-1-and-its-ligands-in-the-liver-of-biliary-atresia
#14
Pan-Liang Wang, Jun Wang, Ying Zhou, Xiao-Song Chen, Ke-Jun Zhou, Jie Wen, Jian-Jun Zhang, Wei Cai
BACKGROUND: An aberrant immune response is the predominant pathogenetic factor in biliary atresia (BA). Programmed death-1 (PD-1) and its two ligands, programmed death ligand-1 and programmed death ligand-2 (PD-L1 and PD-L2, respectively) play an important inhibitory role in immune reactions. We aimed to illustrate the expression of these molecules in BA. METHODS: Liver specimens were obtained from infants with BA during the Kasai procedure (early BA) and liver transplantation (late BA)...
March 22, 2017: World Journal of Pediatrics: WJP
https://www.readbyqxmd.com/read/28317872/preclinical-evaluation-of-the-efficacy-pharmacokinetics-and-immunogenicity-of-js-001-a-programmed-cell-death-protein-1-pd-1-monoclonal-antibody
#15
Jie Fu, Fang Wang, Li-Hou Dong, Jing Zhang, Cheng-Lian Deng, Xue-Li Wang, Xin-Yao Xie, Jing Zhang, Ruo-Xian Deng, Li-Bo Zhang, Hai Wu, Hui Feng, Bo Chen, Hai-Feng Song
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28314313/pd-l1-expression-confers-better-prognosis-in-locally-advanced-oral-squamous-cell-carcinoma
#16
Yasunao Kogashiwa, Masanori Yasuda, Hiroyuki Sakurai, Mitsuhiko Nakahira, Yoshie Sano, Kenji Gonda, Tetsuya Ikeda, Hitoshi Inoue, Kiyomi Kuba, Susumu Oba, Junichi Ishikawa, Yuichiro Enoki, Satoko Matsumura, Kazuhiko Minami, Yasuhiro Ebihara, Masashi Sugasawa
BACKGROUND/AIM: Clinical trials with therapies targeting immune checkpoint molecules have shown promising results in several tumor types. However, the predictive and prognostic values of these immunological factors for locally advanced oral squamous cell carcinomas (LAOSCC) remain unclear. Our purpose was to evaluate the expression and prognostic value of programmed cell death-ligand1 (PD-L1) and PD-L2 and to correlate their expression with the degree of infiltration by CD8(+) cells in LAOSCC...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28291636/correlation-between-messenger-rna-expression-and-protein-expression-of-immune-checkpoint-associated-molecules-in-bladder-urothelial-carcinoma-a-retrospective-study
#17
Constance Le Goux, Diane Damotte, Sophie Vacher, Mathilde Sibony, Nicolas Barry Delongchamps, Anne Schnitzler, Benoit Terris, Marc Zerbib, Ivan Bieche, Géraldine Pignot
OBJECTIVES: Immunotherapy for bladder cancer seems to have promising results. Here, we evaluated the association between messenger RNA (mRNA) and protein levels and possible prognostic value of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immune checkpoint pathways during bladder carcinogenesis. METHODS AND MATERIALS: Tumor samples were obtained from 155 patients (84 with muscle-invasive bladder cancer [MIBC], and 71 non-muscle-invasive bladder cancer [NMIBC]) and normal bladder tissue from 15 patients...
March 10, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28280600/structural-basis-of-a-novel-pd-l1-nanobody-for-immune-checkpoint-blockade
#18
Fei Zhang, Hudie Wei, Xiaoxiao Wang, Yu Bai, Pilin Wang, Jiawei Wu, Xiaoyong Jiang, Yugang Wang, Haiyan Cai, Ting Xu, Aiwu Zhou
The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids...
2017: Cell Discovery
https://www.readbyqxmd.com/read/28270509/in-situ-and-in-silico-kinetic-analyses-of-programmed-cell-death-1-pd-1-receptor-programmed-cell-death-ligands-and-b7-1-protein-interaction-network
#19
Kaitao Li, Xiaoxiao Cheng, Andreas Tilevik, Simon J Davis, Cheng Zhu
Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance and is among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1 requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-ligands/B7-1 system...
April 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28265006/characterization-of-the-anti-pd-1-antibody-regn2810-and-its-antitumor-activity-in-human-pd-1-knock-in-mice
#20
Elena Burova, Aynur Hermann, Janelle Waite, Terra Potocky, Venus Lai, Seongwon Hong, Matt Liu, Omaira Allbritton, Amy Woodruff, Qi Wu, Amanda D'Orvilliers, Elena Garnova, Ashique Rafique, William Poueymirou, Joel Martin, Tammy Huang, Dimitris Skokos, Joel Kantrowitz, Jon Popke, Markus Mohrs, Douglas MacDonald, Ella Ioffe, William Olson, Israel Lowy, Andrew Murphy, Gavin Thurston
The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen presenting cells and cancer cells, resulting in suppression of T cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 (S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2...
March 6, 2017: Molecular Cancer Therapeutics
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