Clipboard, Search History, and several other advanced features are temporarily unavailable.  DT, Uram  M, Denkert This might have been caused by the spatially more heterogeneous nature of PD-L1 expression than copy number,22,37 which was particularly relevant for this study because of the small biopsy specimens used in most cases. Poor outcome with anti-programmed death-ligand 1 (PD-L1) antibody due to poor pharmacokinetic properties in PD-1/PD-L1 blockade-sensitive mouse models. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).  S, Okamoto PD-L1 copy number was assessed by centrally performed FISH using the Histra PD-L1 FISH kit (Jokoh, Tokyo, Japan) as described elsewhere.22,28 This kit contains the spectrum orange-labeled bacterial artificial chromosome clone RP11-599H20 (9p24.1, PD-L1; Advanced GenoTechs) and the spectrum green-labeled control centromere enumeration probe for chromosome 9 (CEP9; RP11-113O24; Advanced GenoTechs) as PD-L1 locus–specific and referenced chromosome 9 FISH probes, respectively.  SJ, Gøtzsche Â, Miao  E, Water molecules are shown as red spheres.  S, Pretreatment tumor samples were collected for biomarker evaluation. Overall Survival of Patients Stratified by PD-L1 Protein Expression, eTable. The findings of this study suggest that PD-L1 amplification in non–small cell lung cancer is associated with durable benefit from nivolumab treatment. 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).  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. , Friedman An OS benefit for patients with high expression of PD-L1 compared with those with low expression of PD-L1 was observed at the PD-L1 TPS threshold of 50% (HR, 0.44; 95% CI, 0.23-0.84; P = .01) (eFigure 8A in the Supplement), but again, no significant benefit was observed at lower PD-L1 TPS thresholds (eFigures 8B, 8C, and 8D in the Supplement).  V, This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. Correlation coefficients between continuous variables of biomarkers were calculated according to Spearman. Dublin, Oct. 09, 2020 (GLOBE NEWSWIRE) -- The "Programmed Death-Ligand 1 (PD-L1) Non-Small Cell Lung Cancer (NSCLC)-Market Insights, Epidemiology and Market Forecast - 2030" …  Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. , Champiat  JN, Smith  D, Margolis Although patients with PD-L1 polysomy did not demonstrate improved ORR (18.5% [95% CI, 6.3%-38.1%]) compared with those without PD-L1 CNGs, 4 of 5 patients (80.0% [95% CI, 28.4%-99.5%]) with PD-L1 amplification showed response, among whom median duration of response was not reached. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months.  RH, Ligon  et al; PACIFIC Investigators. The structural rearrangement within the CC′ loop upon complex formation is clearly discernible.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via, Yoshimura  KS, Lenkiewicz 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). Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1) inhibitors are the therapeutic candidates or drugs, popularly known as checkpoint inhibitors, used most commonly for … Residues forming the hydrophobic core are colored yellow. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy.  MM, 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.  H,  CF, Proverbs-Singh  SJ, Villegas 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. Programmed cell death protein 1, also known as PD-1 and CD279 (cluster of differentiation 279), is a protein on the surface of cells that has a role in regulating the immune system 's response to the cells …  L, Ammari All residues important for the interaction are highlighted as sticks.  et al. Dr Suda reported receiving grants from Boehringer Ingelheim, AstraZeneca, Takeda Pharmaceutical Company, Kyorin Pharmaceutical Company, Shionogi and Co, Taiho Phamaceutical Co, Daiichi Sankyo Healthcare, and Pfizer outside the submitted work. 2020 Oct 9;5(41):26914-26923. doi: 10.1021/acsomega.0c04149.  F, Waterkamp  K, Conflict of Interest Disclosures: Dr Inui reported receiving grants from Chugai Pharmaceutical Co, Eli Lilly Japan, and MSD KK outside the submitted work.  et al. Responses among patients with PD-L1 amplification were long lasting, leading to excellent progression-free and overall survival outcomes. The significance of PD-L1 CNGs in the context of ICI therapy was originally highlighted in a previous study showing a high rate (87%) of response to nivolumab, including 17% complete response in heavily pretreated Hodgkin lymphoma32 that usually carries a very low level of TMB,33 given that all tumors analyzed by FISH had an increased PD-L1 gene dosage. See this image and copyright information in PMC. This prospective, multicenter, investigator-initiated cohort study enrolled patients from 14 hospitals in Japan between July 1, 2016, and December 11, 2018.  Pembrolizumab versus chemotherapy for, Antonia Copyright © 2015 Elsevier Ltd. All rights reserved. Characteristics of Patients with PD-L1–Amplified Tumors. J Med Chem. 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. 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). A 2-tailed P < .05 was considered statistically significant. The PD-1 receptor inhibits innate and adaptive immunity when upregulated on immune cells. Response to Nivolumab According to PD-L1 Protein Expression, eFigure 7. 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.  Y. 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. Choi JG, Kim YS, Kim JH, Kim TI, Li W, Oh TW, Jeon CH, Kim SJ, Chung HS. 4 Binding of PD-1 to its ligand PD-L1 expressed on … Data were analyzed from December 2019 to February 2020. Based on the encouraging preclinical and clinical studies suggesting the promise of PD-1 axis blockade in PD-L1–amplified tumors, we examined whether increased PD-L1 gene dosage in NSCLC tumors is associated with a greater magnitude of efficacy of nivolumab. Micrographshowing a PD-L1 negative NSCLC.  M, Data were analyzed from December 2019 to February 2020. Additional Contributions: The authors would like to acknowledge patients and their families and Naoko Yoshida and Hisaki Igarashi (Hamamatsu University School of Medicine) for their excellent technical assistance. Close-Up Views of the hPD-1/hPD-L1…, Figure 2.  DS, Koelzer Indeed, previously treated patients with NSCLC who had PD-L1 expression of at least 50% had more response to pembrolizumab compared with those with PD-L1 expression between 1% and 50%.3 However, in our study, PD-L1 expression was relatively low (TPS, ≤15%) in 2 of 5 PD-L1–amplified tumors.  S. Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. For PD-L1 IHC, 118 (60.8%) and 76 (39.2%) samples were assessed using the E1L3N and 22C3 antibodies, respectively.  Atezolizumab versus docetaxel in patients with previously treated non–small cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. , Reck 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 …  Response to Nivolumab According to Programmed Death Ligand 1 (, Table. 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.  P, No patients received ICIs before nivolumab. All Rights Reserved. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error.  Nivolumab versus docetaxel in advanced squamous-cell non–small cell lung cancer. , Borghaei Among the 200 patients enrolled in this study, 6 patients were excluded due to poor-quality tumor specimens for FISH (5 [83.3%]) or both FISH and IHC (1 [16.7%]), resulting in 194 assessable patients. All patients provided written informed consent. Front Immunol.  PC, Harview BMC Bioinformatics. This patient received 21 cycles of nivolumab with a PFS of 9.7 months (eTable in the Supplement).  C, Marabelle Gly124 Cleft ( L Tyr123-Accommodating Cavity) and CC′ Loop Rearrangement Are Induced by…, Figure 4.  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 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. 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. 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). (A) Front-side view.  DM,  JE, Rimm Cox univariable proportional hazards regression model was used to explore the prognostic value of covariables. Targeting the programmed death-1 pathway in lymphoid neoplasms. Inoue Y, Yoshimura K, Nishimoto K, et al.  A, Barlesi Our website uses cookies to enhance your experience.  Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. , Tumeh  MR, Monti  M, Pocock PD-L1, the major PD-1 ligand… Descriptive Statistics for PD-L1 FISH, eFigure 2. 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.  H, Wooten  Mutational landscape and sensitivity to immune checkpoint blockers. , Goodman We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death‐1 (PD‐1) and its ligand, programmed death‐ligand 1 (PD‐L1), in PD‐1 … Our aim was … doi:10.1001/jamanetworkopen.2020.11818, Is the copy number status of the programmed death ligand 1 (, In this cohort study of 194 patients with non–small cell lung cancer who were treated with nivolumab monotherapy, the proportion of patients with. Both PD-L1 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). Meaning  Programmed cell death 1 (PD-1), a member of the B7 receptor family, is an inhibitory receptor expressed on the surface of T cells.  D, Robinson The Fisher exact test was used for categorical variables. 細胞質内に ITSM …  H.  K, Most patients (184 [94.8%]) received platinum-doublet chemotherapy before nivolumab and received nivolumab as the second line (94 [48.5%]) or third line (55 [28.4%]) of treatment. 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). Progression-Free Survival of Patients Stratified by PD-L1 Protein Expression, eFigure 8. Immunosuppressive drugs have to be taken after organ transplantation, but long-term use of these drugs increases the risks of infection and other serious disorders.  M,  A, Daniel  P, Kim Not all submitted comments are published. Statistical analysis: Inoue, Inui, Karayama, Yasui. PD-L1 is expressed not only on APC, DCs, as well as on activated monocytes and B cells, but also on nonlymphoid … Sequential nivolumab was given on day 1 of a 14-day cycle. First, definite conclusions are still precluded because of the small number of patients with PD-L1 amplification. Overall response rate (ORR) according to the. FISH is advantageous for its ability to discriminate PD-L1 amplification from polysomy.  RS, Baas This study has limitations.  P,  Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. .  K, Inoue Epub 2017 Jun 23. PD-L1 and CEP9 signals are shown in red and green, respectively.  R, Chaput  Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. , Prelaj  M, Pockaj Response was assessed every 4 cycles (ie, 8 weeks) using RECIST version 1.1 by local investigators.  et al.  AM, Piccioni Gly124 Cleft ( L Tyr123-Accommodating…, Figure 3.  et al. 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. Conclusions and Relevance  Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. 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.  EM. Molecular dynamics simulations elucidate conformational selection and induced fit mechanisms in the binding of PD-1 and PD-L1.  N, Besse  et al; OAK Study Group.  MA. 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. Identify all potential conflicts of interest that might be relevant to your comment.  et al.  et al. Computed Tomography Scans Before and After Treatment With Nivolumab in a Patient with PD-L1–Amplified Adenocarcinoma, eFigure 5. C, Violin plot depicting PD-L1 tumor proportion score in association with PD-L1 copy number status. Here, we showed dysregulation of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1… Please enable it to take advantage of the complete set of features! Sequential nivolumab was given on day 1 of a 14-day cycle. In addition, PD-L1 amplification was shown to enhance PD-L1 induction in response to cytokines, such as interferon-γ and tumor necrosis factor α, as adaptive immune resistance in preclinical models of lung and breast cancer.23,24 Moreover, tumor PD-L1 amplification was associated with a specific type of TME, defined by high PD-L1 and CD8A (OMIM 186910) expression.25 This TME characterized by PD-L1–positive tumors and enriched cytotoxic immune cells appears to be associated with response to PD-1/PD-L1 inhibitors.  S, Third, we could not assess TMB and characteristics of the TME, mainly owing to the limited small biopsy samples.  T, Uno  Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274)—associations with gene expression, mutational load, and survival. , Roemer Kaumaya PTP, Guo L, Overholser J, Penichet ML, Bekaii-Saab T. Oncoimmunology. Therefore, identifying additional factors that are robustly associated with response to anti–PD-1/PD-L1 immunotherapy remains a major clinical need. Second, actual PD-L1 status during nivolumab treatment might not be represented because of the interval between sampling and nivolumab therapy initiation. Close-Up Views of the hPD-1/hPD-L1 Interface, hPD-1 and hPD-L1 are represented by blue…, Figure 3.  et al.  Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. , Keenan 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. Oncotarget.  NI,  H, Sanchez-Vega Patients with high expression of PD-L1 showed significantly higher ORR than those with low expressions of PD-L1 at PD-L1 TPS thresholds of 1%, 10%, and 50% (eFigure 6 in the Supplement).