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 … 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.  et al. (B) hPD-1 complexed with hPD-L1. Oncotarget. This study was registered at the UMIN Clinical Trials Registry as UMIN000022505.  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via, Yoshimura  JN, Wang This site needs JavaScript to work properly. The ORR among patients with and without PD-L1 CNGs was 28.1% (95% CI, 13.7%-46.7%) and 17.9% (95% CI, 12.3%-24.7%), respectively. We hypothesized that adverse events …  H, Paz-Ares 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 …  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. , Le  M, Pockaj 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. In contrast to our hypothesis that low-grade PD-L1 CNGs represented as polysomy would derive limited benefit from nivolumab therapy, no benefit in response and survival was observed, suggesting distinct roles for PD-L1 amplification and polysomy in tumor immune evasion. Sequential nivolumab was given on day 1 of a 14-day cycle. Data were analyzed from December 2019 to February 2020. iScience. No other disclosures were reported. 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. They were not compensated for their time.  T, Okano Three Main Hot Spots on the PD-L1 Surface, NLM Gly124 Cleft ( L Tyr123-Accommodating Cavity) and CC′ Loop Rearrangement Are Induced by…, Figure 4.  et al; OAK Study Group. Of the 4 patients with PD-L1 amplification who responded to therapy, 3 patients were still receiving study treatment at the final database lock.  et al.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. , Friedman  Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. .  JJ, Makarov  Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. , Ansell  VH, Herzig  et al.  Tumor and microenvironment evolution during immunotherapy with nivolumab. , Thommen 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. (A) Apo-hPD-1. 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 … A 2-tailed P < .05 was considered statistically significant. We reported associations between programmed death ligand-1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS after nivolumab treatment. PD-L1 expression was regarded as positive if membranous expression at any intensity was observed.  NA, Hellmann  JC, Postel-Vinay This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. Identify all potential conflicts of interest that might be relevant to your comment. The associations of tumor PD-L1 protein expression with PD-L1 copy number and outcomes were also included in the secondary end points. The findings of this study suggest that PD-L1 amplification in non–small cell lung cancer is associated with durable benefit from nivolumab treatment. 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.  Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. , Champiat Question  Representative images of fluorescence in situ hybridization analysis of tumors carrying PD-L1 disomy, polysomy, or amplification obtained from patients enrolled in this study (original magnification ×100). This patient received 21 cycles of nivolumab with a PFS of 9.7 months (eTable in the Supplement). Design, Setting, and Participants   Y. 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.  D, Margolis ¥çš„に作った抗体で蓋をしてしまうことで結合を阻害しT細胞を抑制させない薬が認可され … Conclusions and Relevance  Of note, the 5 PD-L1–amplified tumors exhibited various PD-L1 TPS values, ranging from 4% to 95% (eTable in the Supplement). Hydrogen bonds are depicted as black dashed lines. 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. Nivolumab was repeatedly administered intravenously on day 1 of each 14-day cycle until progressive disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; discontinuation as a result of unacceptable adverse event; or withdrawal of consent. The primary end point was the difference in overall response rate (ORR), defined as partial response plus complete response using RECIST version 1.1, according to the PD-L1 copy number status; secondary end points included the differences in progression-free survival (PFS) and overall survival (OS) based on PD-L1 copy number status. 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. 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. At final database lock on December 9, 2019, the median (interquartile range [IQR]) follow-up was 12.6 (5.6-20.4) months, and 127 patients (65.5%) had died, with study treatment ongoing among 16 patients (8.2%). hPD-1 and hPD-L1 are represented by blue and green ribbons, respectively.  R, Chaput Within the complex structure, hPD-1 is colored blue and hPD-L1 is colored green; both are shown in stereo view in ribbon representation. Â, Miao (A and B) Surface representation of the hPD-L1 binding site of hPD-1.  Genomic correlates of response to immune checkpoint blockade. , Green 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. 3D rendering. By continuing to use our site, or clicking "Continue," you are agreeing to our, 2020 American Medical Association.  J, Bockmayr  CL, Yearley 2017 Jul 13;60(13):5857-5867. doi: 10.1021/acs.jmedchem.7b00293.  JE, Rimm Understanding the Targeting Mechanisms of Multi-Specific Biologics in Immunotherapy with Multiscale Modeling.  D, Kato Baseline patient and tumor characteristics are given in the Table. Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non–small Cell Lung Cancer. 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. 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). …  TA, Postow First, definite conclusions are still precluded because of the small number of patients with PD-L1 amplification.  K, Mori  S, Dercle  Nivolumab versus docetaxel in advanced nonsquamous non–small cell lung cancer. . 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).  Clinical significance of PD-L1 and PD-L2 copy number gains in non–small cell lung cancer. , Ikeda USA.gov.  et al. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Supervision: Inui, Karayama, Hozumi, Suzuki, Enomoto, Sugimura, Suda.  et al. NIH El ligando 1 de muerte programada (en inglés: Programmed Death-ligand 1, PD-L1), cúmulo de diferenciación 274 (CD274) u homólogo 1 de B7 (en inglés: B7 homolog 1, B7-H1) es una proteína, … T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection. Get free access to newly published articles. Copyright © 2015 Elsevier Ltd. All rights reserved. JAMA Network Open. As a result, median duration of response was not reached (range, 17.7 [ongoing] to 33.7 [ongoing] months) for patients with PD-L1 amplification who responded, which was longer than that among patients with PD-L1 polysomy who responded (14.9 months; 95% CI, 4.6 months to not reached) or those with disomy who responded (16.8 months; 95% CI, 8.1 months to not reached) (eFigure 3A in the Supplement).  Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274)—associations with gene expression, mutational load, and survival. , Roemer  JH,  |  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. 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.  KS, Lenkiewicz Please enable it to take advantage of the complete set of features! 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.