N, Havel Accessibility Statement, Figure 1. 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. Understanding the Targeting Mechanisms of Multi-Specific Biologics in Immunotherapy with Multiscale Modeling. A 2-tailed P < .05 was considered statistically significant.  A, Daniel Responses among patients with PD-L1 amplification were long lasting, leading to excellent progression-free and overall survival outcomes.  DS, Koelzer Kaumaya PTP, Guo L, Overholser J, Penichet ML, Bekaii-Saab T. Oncoimmunology.  C, Marabelle  Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. , Prelaj  H, Paz-Ares  et al.  I, Patients with PD-L1 amplification showed excellent survival outcomes for progression-free and overall survival. USA.gov. hPD-1 and hPD-L1 are represented by blue and green ribbons, respectively.  |   M,  JN, Smith 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.  PD-L1 Is upregulated by simultaneous amplification of the, Chen 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%).  CA, Vokes Waterfall Plot Showing the Best Percentage Change From Baseline, eFigure 6. External validation with a larger sample size is warranted to facilitate personalization of PD-1/PD-L1 blockade for patients with NSCLC. Main Outcomes and Measures   P, Kim 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.  H, Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). 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.  et al. If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. 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.  M, Denkert Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 4.0. Representative computed tomography scans demonstrating response in a patient with PD-L1–amplified adenocarcinoma are shown in eFigure 4 in the Supplement.  S, Rodig Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.27.  Fluorescence In Situ Hybridization Analysis of Programmed Death Ligand 1 (, Figure 3. Terms of Use| iScience. 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. Future studies will need to investigate the evolving PD-L1 genetic complexity in cancer cells.  TA, Postow In this study, a selection of patients with NSCLC based on PD-L1 amplification was associated with greater durable benefit from nivolumab. 2020 Nov 5;11:598556. doi: 10.3389/fimmu.2020.598556.  SJ, Our website uses cookies to enhance your experience.  JN, Wang PD-L1 amplification was defined as a PD-L1 to CEP9 ratio of at least 2.0; polysomy was defined as a mean PD-L1 signal of at least 3.0 and a PD-L1 to CEP9 ratio of less than 2.0; other tumors were defined as disomy.22. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Response to Nivolumab According to PD-L1 Protein Expression, eFigure 7.  Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. , Skoulidis  A, Soria Please allow up to 2 business days for review, approval, and posting.  K, We also acknowledge the following pathologists in the participant hospitals; Satoshi Baba, MD, PhD (Hamamatsu University School of Medicine), Makoto Suzuki, MD, PhD (Shizuoka General Hospital), Fumihiko Tanioka, MD, PhD (Iwata City Hospital), Akira Moriki, MD, PhD (Shizuoka City Shizuoka Hospital), Hiroshi Ogawa, MD, PhD (Seirei Mikatahara General Hospital), Kenji Koda, MD, PhD (Fujieda Municipal General Hospital), Toshiro Otsuki, MD, PhD (Seirei Hamamatsu General Hospital), Yasuhiko Kitayama, MD, PhD (Shizuoka Saiseikai General Hospital), Masato Nakamura, MD, PhD (Shizuoka City Shimizu Hospital), Takashi Uemura, MD (Ensyu Hospital), Hiroki Mori, MD, PhD (Hamamatsu Medical Center). Kuang Z, Heng Y, Huang S, Shi T, Chen L, Xu L, Mei H. ACS Omega.  et al. Funding/Support: This was an investigator-initiated study supported by Ono Pharma and Bristol-Myers Squibb.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. , Sugimura We hypothesized that adverse events … Privacy Policy|  |  Overall response rate (ORR) according to the.  et al.  et al.  S, Supervision: Inui, Karayama, Hozumi, Suzuki, Enomoto, Sugimura, Suda.  K, Most patients were men (155 [79.9%]) and had a history of smoking (162 [83.5%]), PS 0 or 1 (186 [95.9%]), and stage IV disease (136 [70.6%]).  MD, Nathanson  M, Lefebvre  et al. Inoue Y, Yoshimura K, Nishimoto K, et al.  et al; KEYNOTE-024 Investigators. This patient received 21 cycles of nivolumab with a PFS of 9.7 months (eTable in the Supplement). (B) hPD-1 complexed with hPD-L1.  L, Ammari PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy. Regulatory approval of pembrolizumab for treatment of gastric and gastroesophageal junction (G/GEJ) adenocarcinoma required a reproducible scoring method for use of programmed death ligand-1 (PD …  DL, The Kruskal-Wallis test was used for continuous variables, followed by adjustment using the method of Holm. Water molecules are shown as red spheres. 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). Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1.  R, Ferrara 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.  Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. , Inoue Results  C, Violin plot depicting PD-L1 tumor proportion score in association with PD-L1 copy number status. Importance   N, Besse 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.  et al.  R, Chaput  RH, Ligon Sequential nivolumab was given on day 1 of a 14-day cycle.  M, Pockaj 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.  EM. 237 Cancers take advantage of this mechanism to induce a local immunosuppression by overexpressing PD-L1.  Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274)—associations with gene expression, mutational load, and survival. , Roemer Data were analyzed from December 2019 to February 2020.  M, 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. 2016 May 24;7(21):30323-35. doi: 10.18632/oncotarget.8730. Gly124 Cleft ( L Tyr123-Accommodating…, Figure 3.  Pembrolizumab versus docetaxel for previously treated, Rittmeyer 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.  F, La Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. 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? J Med Chem.  Tumor and microenvironment evolution during immunotherapy with nivolumab. , Thommen Residues forming the hydrophobic core are colored yellow. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 2020 Oct 9;5(41):26914-26923. doi: 10.1021/acsomega.0c04149. JAMA Netw Open. 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 … 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. 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.  JC, Postel-Vinay Pretreatment tumor samples were collected for biomarker evaluation. Programmed cell death 1 ligand 1 (synonym CD274, B7 Homolog 1) ist ein Oberflächenprotein und beteiligt an der Hemmung der Immunantwort.  T, Rizvi COVID-19 is an emerging, rapidly evolving situation.  AM, Piccioni 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). 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). 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. The PD-1 receptor inhibits innate and adaptive immunity when upregulated on immune cells. 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. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error.  et al. Earlier assessment of progressive disease before 4 cycles was allowed if progression was suspected. eCollection 2020 Dec 18. OS was defined as the interval from the date of the first administration of nivolumab to the date of death from any cause.  SJ, Villegas  et al.  TE, Burke 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.  DG, Egger  JE, Rimm 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. 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, … It is …  S. FISH is advantageous for its ability to discriminate PD-L1 amplification from polysomy. Design, Setting, and Participants  Administrative, technical, or material support: Inoue, Yoshimura, Nishimoto, Inui, Karayama, Furuhashi, Fujisawa, Asada, Uto, Matsui, Hashimoto, Toyoshima, Kusagaya, Sugimura. See this image and copyright information in PMC. Our aim was … We excluded patients with concomitant autoimmune diseases, interstitial lung diseases, uncontrolled symptomatic brain metastases, or other severe uncontrolled complications. Targeting the programmed death-1 pathway in lymphoid neoplasms.  MD, Awad 2020 Nov 20;23(12):101835. doi: 10.1016/j.isci.2020.101835.  H, Sanchez-Vega Programmed cell death 1 (PD-1), a member of the B7 receptor family, is an inhibitory receptor expressed on the surface of T cells. Descriptive Statistics for PD-L1 FISH, eFigure 2. By continuing to use our site, or clicking "Continue," you are agreeing to our, 2020 American Medical Association.  et al; OAK Study Group. PD-L1 immunostain …  S, 4 Binding of PD-1 to its ligand PD-L1 expressed on … 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). HHS  D, 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?  Genomic features of response to combination immunotherapy in patients with advanced non–small cell lung cancer. , Rizvi Overall, 5 (2.6%) and 27 (13.9%) tumors showed PD-L1 amplification and polysomy, respectively; representative FISH images are shown in Figure 1.  JJ, Makarov 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.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. , Friedman We thank the Edanz Group for editing a draft of this article. Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study. PD-L1 and CEP9 signals are shown in red and green, respectively.  |  This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. Programmed death-ligand 1, commonly abbreviated PD-L1, is a protein with an important role in immune system regulation and cancer. Hydrogen bonds are depicted as black dashed lines.  EC, Elledge 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%.  ME, Greenawalt However, this patient subsequently experienced no disease progression until final database lock, receiving no other systemic antitumor therapy.  et al.  et al. External validation with a larger sample size is warranted.  CL, Yearley sign up for alerts, and more, to access your subscriptions, sign up for alerts, and more, to download free article PDFs, sign up for alerts, customize your interests, and more, to make a comment, download free article PDFs, sign up for alerts and more, Archives of Neurology & Psychiatry (1919-1959), Sign Up for Emails Based on Your Interests, FDA Approval and Regulation of Pharmaceuticals, 1983-2018, Global Burden of Skin Diseases, 1990-2017, Health Care Spending in the US and Other High-Income Countries, Life Expectancy and Mortality Rates in the United States, 1959-2017, Medical Marketing in the United States, 1997-2016, Practices to Foster Physician Presence and Connection With Patients in the Clinical Encounter, US Burden of Cardiovascular Disease, 1990-2016, US Burden of Neurological Disease, 1990-2017, Waste in the US Health Care System: Estimated Costs and Potential for Savings, Register for email alerts with links to free full-text articles. The median (IQR) follow-up period among 67 patients who were censored was 20.5 (15.4-30.4) months. This study has limitations.  PC, Harview The associations of tumor PD-L1 protein expression with PD-L1 copy number and outcomes were also included in the secondary end points.  AH,  M, Rodríguez-Abreu Herbst  S, 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. Both PD-L1 Additional end points were progression-free survival, overall survival, and PD-L1 tumor proportion score (TPS) assessed by immunohistochemistry based on PD-L1 copy number status. 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. Statistical analysis: Inoue, Inui, Karayama, Yasui. 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). PD-L1 is encoded by the PD-L1 gene (CD274; OMIM 605402) located on the chromosome band 9p24.1. Baseline patient and tumor characteristics are given in the Table.  Patient and Tumor Characteristics at Baseline, Brahmer Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Dömling A, Dubin G, Holak TA. 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.  et al. Of the 4 patients with PD-L1 amplification who responded to therapy, 3 patients were still receiving study treatment at the final database lock. When referenced to disomy, PD-L1 amplification was associated with a significantly decreased risk of progression (PFS: hazard ratio [HR], 0.10; 95% CI, 0.01-0.72; P = .02), whereas PD-L1 polysomy did not have an association with risks of PFS (HR, 1.19; 95% CI, 0.78-1.83; P = .42) or OS (HR, 1.30; 95% CI, 0.79-2.12; P = .30). This prospective, multicenter, investigator-initiated cohort study enrolled patients from 14 hospitals in Japan between July 1, 2016, and December 11, 2018. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1. Molecular dynamics simulations elucidate conformational selection and induced fit mechanisms in the binding of PD-1 and PD-L1. Guzik K, Zak KM, Grudnik P, Magiera K, Musielak B, Törner R, Skalniak L, Dömling A, Dubin G, Holak TA. Clipboard, Search History, and several other advanced features are temporarily unavailable. Epub 2017 Feb 11. Binding of hPD-L1 Induces Significant…, Figure 1. Survival data were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the differences in survival durations. Gly124 Cleft ( L Tyr123-Accommodating Cavity) and CC′ Loop Rearrangement Are Induced by…, Figure 4. Objective  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%.  B, Califano  T, Uno eCollection 2020 Oct 20. In addition, the benefit observed in patients with PD-L1–amplified tumors irrespective of PD-L1 expression levels suggests other mechanisms that render PD-L1–amplified tumors sensitive to ICIs, including the link with known predictive factors such as TMB. Acquisition, analysis, or interpretation of data: Inoue, Yoshimura, Nishimoto, Inui, Karayama, Yasui, Hozumi, Suzuki, Furuhashi, Fujisawa, Enomoto, Nakamura, Asada, Uto, Fujii, Matsui, Matsuura, Hashimoto, Toyoshima, Kusagaya, Matsuda, Inami, Kaida, Niwa, Ito, Sugimura.  PD-1 blockade in tumors with mismatch-repair deficiency. , Rizvi No patients received ICIs before nivolumab. Characteristics of Patients with PD-L1–Amplified Tumors. In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC.  et al.  MG, Advani Identify all potential conflicts of interest that might be relevant to your comment. The 28-8 anti–PD-L1 antibody (Abcam) and FLAG-M2 monoclonal antibody (Sigma-Aldrich) were applied for the validation study.  First-line nivolumab plus ipilimumab in advanced non–small-cell lung cancer (CheckMate 568): outcomes by programmed death ligand 1 and tumor mutational burden as biomarkers. , Davoli  NA, Hellmann  S, Dercle  P, Close-Up Views of the hPD-1/hPD-L1…, Figure 2. 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" … They were not compensated for their time. 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 … Apo-hPD1 (PDB: 3RRQ) was overlaid on hPD-1 within the complex, and residues 62–82 of the former are shown (yellow ribbon). 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. Choi JG, Kim YS, Kim JH, Kim TI, Li W, Oh TW, Jeon CH, Kim SJ, Chung HS. 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 …  P, Close-Up Views of the hPD-1/hPD-L1 Interface, hPD-1 and hPD-L1 are represented by blue…, Figure 3. 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.  R. 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. (A) Front-side view. Of note, the 5 PD-L1–amplified tumors exhibited various PD-L1 TPS values, ranging from 4% to 95% (eTable in the Supplement). Concept and design: Inoue, Yoshimura, Inui, Karayama, Matsuda, Sugimura, Suda. 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). Sequential nivolumab was given on day 1 of a 14-day cycle. 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).  J, Bockmayr They were not compensated for their time. BMC Bioinformatics. © 2020 American Medical Association.  DM, Meeting abstracts Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on lymphoid and non-lymphoid-derived cells that negatively regulates peripheral T-cell responses.  D, Robinson  VH, Herzig  et al.  E, Altman (A) Apo-hPD-1.  N, Hellmann  KP, Van Allen Structural Biology of the Immune Checkpoint Receptor PD-1 and Its Ligands PD-L1/PD-L2. Evaluation of Programmed Death Ligand 1 (PD-L1) Gene Amplification and Response to Nivolumab Monotherapy in Non–small Cell Lung Cancer. No other disclosures were reported. 2020;3(9):e2011818. 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). 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). Cox univariable proportional hazards regression model was used to explore the prognostic value of covariables.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. , Chabanon  Nivolumab versus docetaxel in advanced squamous-cell non–small cell lung cancer. , Borghaei 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 …  et al. 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 …  KL, Baas  PC, Vandenbroucke We reported associations between programmed death ligand-1 (PD-L1) single nucleotide polymorphisms (SNPs) and PFS after nivolumab treatment. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. All Rights Reserved.  et al.  et al. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months. Tumor specimens that contained fewer than 100 tumor cells or showed low quality were excluded from FISH and IHC analyses. eCollection 2020. B, Scatterplot depicting PD-L1 tumor proportion score and PD-L1 to CEP9 ratio (Spearman ρ = 0.12; 95% CI, −0.025 to 0.26; P = .10). 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). 2017 Jul 13;60(13):5857-5867. doi: 10.1021/acs.jmedchem.7b00293. These results justify the clinical application of PD-L1 FISH, considering the strong association of PD-L1 amplification with response to PD-1/PD-L1 blockade. 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.  MD, Snyder 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.

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