programmed death ligand 1 pd l1

 Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non–small cell lung cancer profiled with targeted next-generation sequencing. , Hellmann Responses among patients with PD-L1 amplification were long lasting, leading to excellent progression-free and overall survival outcomes.  Heterogeneity analysis of PD-L1 expression and copy number status in EBUS-TBNA biopsy specimens of non–small cell lung cancer: comparative assessment of primary and metastatic sites. , Ready This could be partially explained by the finding that group-level and chromosome-level somatic copy number alterations are more negatively associated with cytotoxic immune cell infiltration than the other type of tumor aneuploidy, focal somatic copy number alterations, through a putative mechanism of general gene dosage imbalance rather than the action of specific genes.39 Our definitions of amplification and polysomy are more likely to represent focal and group-level or chromosome-level CNGs, respectively. Earlier assessment of progressive disease before 4 cycles was allowed if progression was suspected. Representative computed tomography scans demonstrating response in a patient with PD-L1–amplified adenocarcinoma are shown in eFigure 4 in the Supplement.  Atezolizumab versus docetaxel in patients with previously treated non–small cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. , Reck The interaction between PD … In this cohort study of 194 patients with non–small cell lung cancer who were treated with nivolumab monotherapy, the proportion of patients with PD-L1 amplification who achieved response was 80.0% vs 18.5% among those with PD-L1 polysomy and 17.9% among those with PD-L1 disomy.  JH,  Pembrolizumab versus chemotherapy for, Antonia Privacy Policy|  JJ, Makarov It is … Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years.  Y, Yoshimura Cancer Treat Rev. PFS was defined as the time between the date of the first administration of nivolumab and the date of progression, defined by RECIST version 1.1, or death due to any cause. RESEARCH Open Access Prognostic effect of programmed death-ligand 1 (PD-L1) in ovarian cancer: a systematic review, meta-analysis and bioinformatics study Lin Wang Abstract Background: The … R21 GM087617/GM/NIGMS NIH HHS/United States, R01 GM097082/GM/NIGMS NIH HHS/United States, P41 GM094055/GM/NIGMS NIH HHS/United States, 1P41GM094055/GM/NIGMS NIH HHS/United States, 1R21GM087617/GM/NIGMS NIH HHS/United States, 1R01GM097082/GM/NIGMS NIH HHS/United States, NCI CPTC Antibody Characterization Program. To evaluate whether PD-L1 (CD274) copy number gains (CNGs), comprising amplification and polysomy, in pretreatment specimens assessed by fluorescence in situ hybridization are associated with response to nivolumab monotherapy in NSCLC. This multicenter cohort study enrolled 200 patients, of whom 194 had assessable tumors, with advanced or recurrent NSCLC who were treated with nivolumab after progression following prior treatment at 14 institutions in Japan between July 2016 and December 2018. All PD-L1–amplified tumors were adenocarcinomas without EGFR and ALK alterations that developed in male smokers, except for 1 with squamous histology (eTable in the Supplement). A total of 6 of the 200 patients were excluded because of poor-quality tumor specimens for the biomarker study, resulting in 194 assessable patients. BACKGROUND: Programmed cell death 1 (PD-1) receptor engagement on T cells by its ligand programmed cell death ligand 1 (PD-L1) is a key mechanism of immune escape, and antibody … (A) Front-side view.  EM. Not all submitted comments are published. Objective  Hydrogen bonds are depicted as black dashed lines. All patients received nivolumab monotherapy at a dose of 3 mg/kg; the dosage was changed to a flat 240-mg dose in August 2018, according to the renewed approval by the Japanese Ministry of Health, Labor, and Welfare. PD-L1 immunostain … In terms of survival outcome, we observed only 1 event of progression (Figure 4A) and no deaths (Figure 4B) among patients with PD-L1 amplification, with a 1-year PFS rate of 80.0% (95% CI, 20.4%-96.9%) and 1-year OS rate of 100%.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , von Elm Other names: anti-programmed cell death-1 (PD-1) monoclonal antibodies, immune checkpoint inhibitors, programmed death-ligand 1 (PD-L1) blocking antibodies What are Anti-PD-1 monoclonal antibodies?  MT, Anderson The number of PD-L1 expression–positive cases at different TPS thresholds were 86 (44.3%) at TPS 1%, 73 (37.6%) at TPS 5%, 61 (31.4%) at TPS 10%, and 24 (12.4%) at TPS 50%.  DT, Durham  D, 2016 May 24;7(21):30323-35. doi: 10.18632/oncotarget.8730. BMC Bioinformatics. Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 4.0. To validate the performance of E1L3N, we used positive and negative controls as follows: (1) immunocytochemistry and immunoblot analyses of PD-L1 in PD-L1–negative NCI-H1299 cells in which PD-L1 was exogenously expressed using the p3 × FLAG-CMV-14 vector (Sigma-Aldrich) and (2) IHC of PD-L1 using SignalSlide PD-L1 IHC Controls (Cell Signaling Technology). Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. In contrast, the 1-year PFS and 1-year OS rates were only 18.5% (95% CI, 6.7%-34.8%) and 46.0% (95% CI, 26.4%-63.6%) for patients with PD-L1 polysomy and 20.8% (95% CI, 14.8%-27.4%) and 57.6% (95% CI, 49.6%-64.8%) for patients with PD-L1 disomy, respectively.  S,  et al. … Blockers of the PD-L1 and PD-1 interaction are an important new anticancer drug class.  et al. Overall response rate (ORR) according to the PD-L1 copy number status.  |   CF, Proverbs-Singh They were not compensated for their time.  F, Goldberg  SJ, Gøtzsche  et al; PACIFIC Investigators.  Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-Cell infiltration. , World Medical Association.  T, Uno Censoring was done at the date of last contact.  Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. , Champiat Micrographshowing a PD-L1 negative NSCLC.  et al.  Tumor and microenvironment evolution during immunotherapy with nivolumab. , Thommen eCollection 2020 Oct 20. Although somatic genomic features, such as variations and copy number alterations, have been associated with response and resistance to ICIs,30,31 tumor PD-L1 copy number status has received limited attention in solid tumors. When stratified by the presence of PD-L1 CNGs, there was no significant difference in ORR (with CNGs: 28.1%; 95% CI, 13.7%-46.7%; without CNGs: 17.9%; 95% CI, 12.3%-24.7%; P = .22) (Figure 3A). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.27. Therefore, identifying additional factors that are robustly associated with response to anti–PD-1/PD-L1 immunotherapy remains a major clinical need. Median (range) age at enrollment was 69 (43-83) years. Conclusions and Relevance  However, the ORR among patients with PD-L1 amplification was high (80.0%; 95% CI, 28.4%-99.5%), which was a contrast with the low ORR (18.5%; 95% CI, 6.3%-38.1%) among patients with PD-L1 polysomy (Figure 3B). Published: September 21, 2020. doi:10.1001/jamanetworkopen.2020.11818.  et al. PD-L1 is encoded by the PD-L1 gene (CD274; OMIM 605402) located on the chromosome band 9p24.1.  DG, Egger Several other predictors of responsiveness have also been identified, including mismatch repair deficiency,10,11 tumor mutation burden (TMB),12-14 and tumor-infiltrating immune cells.15-17 However, none of these factors appear to be satisfactorily sensitive or specific, even when multiple factors are combined,18 in part owing to technical issues, the dynamic nature of the TME, and the complexity and heterogeneity of cancer cells.  M, Rodríguez-Abreu However, this patient subsequently experienced no disease progression until final database lock, receiving no other systemic antitumor therapy.  A, Barlesi  PD-1 blockade induces responses by inhibiting adaptive immune resistance. , Riaz  SJ, Villegas  SJ. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. To be eligible for the study, patients for whom nivolumab therapy was planned had to fulfill the following criteria: (1) be aged 18 years or older; (2) have an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2; (3) have histologically proven unresectable stage III or IV or recurrent NSCLC; (4) have progressed following prior treatment; and (5) have available archived formalin-fixed paraffin-embedded tumor for FISH and immunohistochemistry (IHC) analyses of PD-L1.  P, Tumor PD-L1 protein expression was assessed in sections adjacent to those used for FISH by IHC using the E1L3N antibody (Cell Signaling Technology) or the 22C3 pharmDX assay (Agilent) before and after the approval of the 22C3 assay in Japan, respectively, followed by calculation of the tumor proportion score (TPS).  et al; OAK Study Group.  R, Chaput Conflict of Interest Disclosures: Dr Inui reported receiving grants from Chugai Pharmaceutical Co, Eli Lilly Japan, and MSD KK outside the submitted work.  Detection of chromosome changes in pathology archives: an application of microwave-assisted fluorescence in situ hybridization to human carcinogenesis studies. , Kanda The remaining patient with PD-L1 amplification who did not respond obtained stable disease, demonstrating evidence of antitumor effects, with tumor regression of 20%, as shown in the waterfall plot (eFigure 5 in the Supplement).  MD, Snyder We calculated that a group of 200 individuals would contain approximately 40 patients with tumors carrying PD-L1 CNGs, based on a prevalence of approximately 20%.22 Although no formal hypothesis testing was planned, we assumed that ORR to nivolumab would be approximately 30% in patients with tumors harboring PD-L1 CNGs.  B, Califano Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. 2017 Aug 1;25(8):1163-1174. doi: 10.1016/j.str.2017.06.011. Of note, the 5 PD-L1–amplified tumors exhibited various PD-L1 TPS values, ranging from 4% to 95% (eTable in the Supplement). 2017 Jul 13;60(13):5857-5867. doi: 10.1021/acs.jmedchem.7b00293. FISH is advantageous for its ability to discriminate PD-L1 amplification from polysomy. First, definite conclusions are still precluded because of the small number of patients with PD-L1 amplification. Recently, a single-nucleotide polymorphism (SNP) in the programmed death ligand 1 (PD-L1) gene has been associated with Graves’ disease (GD) in a Japanese patient cohort. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). For the other patient with PD-L1 amplification who responded, nivolumab was terminated after 5 cycles because of grade 2 colitis as an adverse effect.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via, Yoshimura Progression-Free Survival of Patients Stratified by PD-L1 Protein Expression, eFigure 8.  NA, Hellmann Close-Up Views of the hPD-1/hPD-L1 Interface, hPD-1 and hPD-L1 are represented by blue…, Figure 3.  et al. Front Immunol. Choi JG, Kim YS, Kim JH, Kim TI, Li W, Oh TW, Jeon CH, Kim SJ, Chung HS.  JP; STROBE Initiative.  Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. , Prelaj Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. We thank the Edanz Group for editing a draft of this article.  JN, Wang  et al.  C, Programmed death-ligand 1 (PD-L1) protein.  KL, Baas PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. Patients with a PD-L1 TPS of at least 50% had a superior median PFS of 8.1 (95% CI, 2.1-20.9) months compared with that of 2.2 (95% CI, 1.8-3.4) months in patients with a TPS of less than 50% (HR, 0.54; 95% CI, 0.33-0.90; P = .02) (eFigure 7A in the Supplement).  K, Inoue  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. , Friedman Sequential nivolumab was given on day 1 of a 14-day cycle. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. Residues forming the hydrophobic core are colored yellow.  MM, グナルの亢進／抑制に働く CD28/CTLA-4 ファミリーに属する、50～55 kDa のI型膜たんぱく質です。. In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC.  S, Programmed cell death 1 (PD-1), a member of the B7 receptor family, is an inhibitory receptor expressed on the surface of T cells.  Fluorescence In Situ Hybridization Analysis of Programmed Death Ligand 1 (, Figure 3. Tumor specimens that contained fewer than 100 tumor cells or showed low quality were excluded from FISH and IHC analyses.  C, Marabelle  Response to Nivolumab According to Programmed Death Ligand 1 (, Table.  DW, Get free access to newly published articles. 2020 Oct 1;9(1):1818437. doi: 10.1080/2162402X.2020.1818437. PD-L1 TPS was only weakly correlated with PD-L1 copy number (ρ = 0.24; 95% CI, 0.10 to 0.37; P < .001) (Figure 2A) and was not correlated with the PD-L1 to CEP9 ratio (ρ = 0.12; 95% CI, −0.025 to 0.26; P = .10) (Figure 2B), despite a significant difference in PD-L1 expression levels according to the PD-L1 copy number status (Figure 2C). Response to Nivolumab According to PD-L1 Protein Expression, eFigure 7.  et al. Design, Setting, and Participants  This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex.  Fluorescence In Situ Hybridization Analysis of Programmed Death Ligand 1 (, Figure 2. Waterfall Plot Showing the Best Percentage Change From Baseline, eFigure 6. Survival data were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the differences in survival durations.  D, Robinson  et al. All residues important for the interaction are highlighted as sticks. We reported associations between programmed death ligand-1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS after nivolumab treatment.  et al. programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) [8].  K,  H, Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. Of the 4 patients with PD-L1 amplification who responded to therapy, 3 patients were still receiving study treatment at the final database lock. C, Violin plot depicting PD-L1 tumor proportion score in association with PD-L1 copy number status. This cohort study evaluates whether the programmed death ligand 1 (PD-L1) gene copy number gains, comprising amplification and polysomy, in pretreatment specimens are associated with …  KN, Structure. Both PD-L1 Overall Survival of Patients Stratified by PD-L1 Protein Expression, eTable. The Kruskal-Wallis test was used for continuous variables, followed by adjustment using the method of Holm.  J, Bockmayr In FISH analysis, the median (range) number of tumor PD-L1 signals was 2.3 (1.6-7.8) (eFigure 1A in the Supplement), and the median (range) PD-L1 to CEP9 ratio was 1.1 (0.78-3.5) (eFigure 1B in the Supplement). This site needs JavaScript to work properly. Correlative Analysis of Response and PD-L1 Expression. 237 Cancers take advantage of this mechanism to induce a local immunosuppression by overexpressing PD-L1. In this study, a selection of patients with NSCLC based on PD-L1 amplification was associated with greater durable benefit from nivolumab. No patients received ICIs before nivolumab. Figure 1.  P,  CY, Keam Programmed death ligand-1（PD-L1）の発現は、さまざまな癌腫において予後不良因子 であるとの報告がなされてきました。しかし近年、乳癌や悪性黒色腫などにおいて、そ の発言が良好な予後と関 … A, Scatterplot depicting the correlation between PD-L1 tumor proportion score and PD-L1 copy number (Spearman ρ = 0.24; 95% CI, 0.10 to 0.37; P < .001). Â, Miao  CL, Yearley PD-L1, the major PD-1 ligand…  Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274)—associations with gene expression, mutational load, and survival. , Roemer This patient received 21 cycles of nivolumab with a PFS of 9.7 months (eTable in the Supplement). Here, we showed dysregulation of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1… Robust predictors for response to anti–programmed death 1 and its ligand (PD-1/PD-L1) immunotherapy in non–small cell lung cancer (NSCLC) are not fully characterized.  K, Mori Data were analyzed from December 2019 to February 2020. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab.  T, Okano We validated the comparative performance of the E1L3N antibody with the referenced antibodies in immunocytochemistry and IHC (eFigure 2A in the Supplement) and Western blot (eFigure 2B in the Supplement) analyses. T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection.  S, Okamoto Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. Is the copy number status of the programmed death ligand 1 (PD-L1) gene in non–small cell lung cancer associated with response to nivolumab monotherapy? Immunogenicity and antitumor efficacy of a novel human PD-1 B-cell vaccine (PD1-Vaxx) and combination immunotherapy with dual trastuzumab/pertuzumab-like HER-2 B-cell epitope vaccines (B-Vaxx) in a syngeneic mouse model.  Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. , Keenan  et al. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor.  et al. Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1.  Pembrolizumab versus docetaxel for previously treated, Rittmeyer Data were analyzed from December 2019 to February 2020.  N, Besse Apo-hPD1 (PDB: 3RRQ) was overlaid on hPD-1 within the complex, and residues 62–82 of the former are shown (yellow ribbon).  |  Close-Up Views of the hPD-1/hPD-L1…, Figure 2. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.  TA, Postow Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. The mechanisms by which PD-L1–amplified tumors are associated with long-lasting responses to nivolumab remain unclear. Administrative, technical, or material support: Inoue, Yoshimura, Nishimoto, Inui, Karayama, Furuhashi, Fujisawa, Asada, Uto, Matsui, Hashimoto, Toyoshima, Kusagaya, Sugimura. Three Main Hot Spots on the PD-L1 Surface, NLM  Nivolumab versus docetaxel in advanced squamous-cell non–small cell lung cancer. , Borghaei (A) Apo-hPD-1. Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) or its ligand (PD-L1) have offered a subset of cancer patients profound and durable survival benefit and transformed the therapeutic landscape of multiple tumor types, particularly in non–small cell lung cancer (NSCLC).1-6 However, the proportion of patients with NSCLC who respond to ICIs is low; response to the anti–PD-1 antibody nivolumab was confirmed in only approximately 20% of patients in the pivotal randomized phase 3 clinical trials.1,2 More troublesome, PD-1/PD-L1 inhibitors can cause immune-related adverse effects7 as well as hyperprogressive disease.8 Therefore, there have been substantial attempts to discover and validate predictive biomarkers to identify patients who may benefit from PD-1/PD-L1 inhibitors by integrating information from tumors, the tumor microenvironment (TME), and the host immune system.9 To date, tumor PD-L1 expression using companion diagnostics is the only approved biomarker to indicate NSCLC patients for PD-1 axis blockade.  AG, Overall, 3 PD-L1-amplified tumors (60.0%) showed PD-L1 TPS of at least 80%, but 2 (40.0%) had PD-L1 TPS of 15% or less.  Y, Karayama No other disclosures were reported. 細胞質内に ITSM …  Clinical significance of PD-L1 and PD-L2 copy number gains in non–small cell lung cancer. , Ikeda  MD, Nathanson … to download free article PDFs, By contrast, there were no significant differences in duration of PFS when stratified by lower PD-L1 TPS thresholds of 10% (eFigure 7B in the Supplement), 5% (eFigure 7C in the Supplement), and 1% (eFigure 7D in the Supplement).  et al. Critical revision of the manuscript for important intellectual content: Inoue, Yoshimura, Nishimoto, Inui, Karayama, Fujisawa, Enomoto, Nakamura, Asada, Uto, Fujii, Matsui, Matsuura, Toyoshima, Kusagaya, Matsuda, Kaida, Niwa, Ito, Sugimura.  M, Programmed cell death 1 (PD‐1)/PD‐ligand 1(PD‐L1) inhibitors‐related pneumonitis in patients with advanced non–small cell lung cancer Yuxin Sun Department of Pulmonary and Critical … Despite being hampered by the low prevalence, this association appears to be more clinically meaningful than selection of patients based on PD-L1 expression at any threshold applied. © 2020 American Medical Association.  et al. (B) hPD-1 complexed with hPD-L1. PD-L1 indicates programmed death ligand 1. eFigure 1. This study was registered at the UMIN Clinical Trials Registry as UMIN000022505. Biomarker evaluation samples were obtained mainly from primary lesions through several procedures, and the median (IQR) interval between the date of sample collection and nivolumab therapy initiation was 10.7 (5.8-16.8) months, with 111 samples (57.2%) collected within 12 months before treatment. 2020 Nov 20;23(12):101835. doi: 10.1016/j.isci.2020.101835.  CA, Vokes Computed Tomography Scans Before and After Treatment With Nivolumab in a Patient with PD-L1–Amplified Adenocarcinoma, eFigure 5. Guzik K, Zak KM, Grudnik P, Magiera K, Musielak B, Törner R, Skalniak L, Dömling A, Dubin G, Holak TA.  R, Ferrara PD-L1 expression was regarded as positive if membranous expression at any intensity was observed. Genomic amplification of this locus is associated with distinct features in multiple tumor types.19-21 We previously reported that PD-L1 copy number gains (CNGs), including amplification and polysomy, as determined by fluorescence in situ hybridization (FISH), were associated with greater PD-L1 expression in NSCLC,22 suggesting that PD-L1 CNGs are responsible for innate immune resistance through constitutive upregulation of PD-L1.  S, Epub 2017 Feb 11. Pretreatment tumor samples were collected for biomarker evaluation.  Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. . Response was assessed every 4 cycles (ie, 8 weeks) using RECIST version 1.1 by local investigators. For the overall population, the ORR and disease control rate was 19.6% (95% CI, 14.2%-25.9%) and 50.5% (95% CI, 43.3%-57.8%), respectively.

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