PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. , Barrett 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. JAMA Network Open. Â, Miao Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance.  D, Corresponding Author: Naoki Inui, MD, PhD, Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan (inui@hama-med.ac.jp).  et al. Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study.  Y, Yoshimura  et al. Nivolumab was discontinued in 178 patients (91.8%), mainly due to disease progression (135 [69.6%]) and adverse events (37 [19.1%]). All patients provided written informed consent. Programmed death ligand 1(PD-L1) is a critical molecule that inhibits immune responses through its receptor, programmed death-1(PD-1), which is expressed on different immune cells. 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. 2020 Oct 9;5(41):26914-26923. doi: 10.1021/acsomega.0c04149. Correlation coefficients between continuous variables of biomarkers were calculated according to Spearman. PD-L1, the major PD-1 ligand… 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. Micrographshowing a PD-L1 negative NSCLC. Please enable it to take advantage of the complete set of features!  D, Robinson The Fisher exact test was used for categorical variables. USA.gov. Responses among patients with PD-L1 amplification were long lasting, leading to excellent progression-free and overall survival outcomes. © 2020 American Medical Association. 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). ¥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 … See this image and copyright information in PMC. By continuing to use our site, or clicking "Continue," you are agreeing to our, 2020 American Medical Association.  E, Altman This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. Design, Setting, and Participants   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 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. Of the 4 patients with PD-L1 amplification who responded to therapy, 3 patients were still receiving study treatment at the final database lock. Response was assessed every 4 cycles (ie, 8 weeks) using RECIST version 1.1 by local investigators.  et al. Computed Tomography Scans Before and After Treatment With Nivolumab in a Patient with PD-L1–Amplified Adenocarcinoma, eFigure 5. Response was assessed every 4 cycles using Response Evaluation Criteria in Solid Tumors version 1.1.  Fluorescence In Situ Hybridization Analysis of Programmed Death Ligand 1 (, Figure 2.  L, Ammari  Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. , Ansell First, it is shown that the ligand binding to human PD-1 is associated with … 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.  et al.  et al. Therefore, identifying additional factors that are robustly associated with response to anti–PD-1/PD-L1 immunotherapy remains a major clinical need.  MD, Awad  S,  K, Mori Binding of hPD-L1 Induces Significant Structural Rearrangements within the Structure of hPD-1, Figure 2. 2017 Mar;54:99-109. doi: 10.1016/j.ctrv.2017.01.009.  D, Kato 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,  KN,  |  All Rights Reserved. Progression-Free Survival of Patients Stratified by PD-L1 Protein Expression, eFigure 8. 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. Third, we could not assess TMB and characteristics of the TME, mainly owing to the limited small biopsy samples. eCollection 2020. Overall response rate (ORR) according to the. 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%. Water molecules are shown as red spheres. The "Programmed Death-Ligand 1 (PD-L1) Non-Small Cell Lung Cancer (NSCLC)-Market Insights, Epidemiology and Market Forecast - 2030" drug pipelines has been added to …  EM.  et al.  S, Stein  Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. , Prelaj 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. Of these, 155 (79.9%) were men, with a median (range) age of 69 (43-83) years. T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection. Baseline patient and tumor characteristics are given in the Table. Close-Up Views of the hPD-1/hPD-L1…, Figure 2. 2020 Dec 14;21(Suppl 17):557. doi: 10.1186/s12859-020-03904-9.  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 PD-L1 is expressed not only on APC, DCs, as well as on activated monocytes and B cells, but also on nonlymphoid … (A) Front-side view. PD-L1 is a transmembrane protein that belongs to the Ig superfamily consisting of an extracellular N-terminal V domain (IgV) and one C domain (IgC) connected by a short linker.1 H-15 N … 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. 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).  P, Kim  et al. Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. The associations of tumor PD-L1 protein expression with PD-L1 copy number and outcomes were also included in the secondary end points. 4 Binding of PD-1 to its ligand PD-L1 expressed on …  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. , Friedman 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). 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" …  A, Daniel  SM, Lesokhin  J, Reckamp  PD-L1 Is upregulated by simultaneous amplification of the, Chen 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. NIH  MT, Anderson Administrative, technical, or material support: Inoue, Yoshimura, Nishimoto, Inui, Karayama, Furuhashi, Fujisawa, Asada, Uto, Matsui, Hashimoto, Toyoshima, Kusagaya, Sugimura.  Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer. , Inoue 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。.  et al; PACIFIC Investigators. Overall Survival of Patients Stratified by PD-L1 Protein Expression, eTable.  MD, Snyder 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. Waterfall Plot Showing the Best Percentage Change From Baseline, eFigure 6. Published: September 21, 2020. doi:10.1001/jamanetworkopen.2020.11818. The PD-1 receptor inhibits innate and adaptive immunity when upregulated on immune cells. Blockers of the PD-L1 and PD-1 interaction are an important new anticancer drug class.  MG, Advani  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. , Chabanon Data were analyzed from December 2019 to February 2020.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. , von Elm There was a positive and statistically significant correlation between PD-L1 signals and the PD-L1 to CEP9 ratio (ρ = 0.61; 95% CI, 0.51-0.70; P < .001) (eFigure 1C in the Supplement). 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. to download free article PDFs,  S,  et al. 2017 Aug 1;25(8):1163-1174. doi: 10.1016/j.str.2017.06.011. 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. The interaction between PD … 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).  L,  MM,  AH, Descriptive Statistics for PD-L1 FISH, eFigure 2. 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. 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.  JE, Rimm  KL, Baas Overall response rate (ORR) according to the PD-L1 copy number status.  PD-1 blockade induces responses by inhibiting adaptive immune resistance. , Riaz  et al. (A and B) Surface representation of the hPD-L1 binding site of hPD-1. 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%. However, the reported very low prevalence (0.7%) of PD-L1 amplification, defined as at least 6 copies, assessed by comprehensive genomic profiling across more than 100 types of solid tumors,34 has been considered a major limitation of its widespread use in clinical practice.35 Nevertheless, our previous report22 and the present study showed that PD-L1 amplification was detected in approximately 3% of patients with NSCLC as assessed by FISH.  JP; STROBE Initiative.  H,  S, Dercle  L, Horn Targeting programmed death-1 and programmed death-ligand 1 (PD-1/PD-L1) in breast cancer appears increasingly appealing after the success of such an approach in other cancers. The information will be posted with your response. Of note, the 5 PD-L1–amplified tumors exhibited various PD-L1 TPS values, ranging from 4% to 95% (eTable in the Supplement). Identify all potential conflicts of interest that might be relevant to your comment.  T, Okano  Detection of chromosome changes in pathology archives: an application of microwave-assisted fluorescence in situ hybridization to human carcinogenesis studies. , Kanda  Nivolumab versus docetaxel in advanced nonsquamous non–small cell lung cancer. . In this study, tumor PD-L1 amplification but not polysomy was associated with response to nivolumab monotherapy among patients with NSCLC. 2020 Nov 5;11:598556. doi: 10.3389/fimmu.2020.598556. Median (interquartile range) duration of follow-up was 12.6 (5.6-20.4) months.  K, 2020;3(9):e2011818.  MD, Nathanson 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).  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. , Le We hypothesized that adverse events … Epub 2017 Jun 23. We thank the Edanz Group for editing a draft of this article. The structural rearrangement within the CC′ loop upon complex formation is clearly discernible. Zak KM, Grudnik P, Guzik K, Zieba BJ, Musielak B, Dömling A, Dubin G, Holak TA. Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. 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. Our aim was … 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%]). Terms of Use|  F, La Objective  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. 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).  et al. Accessibility Statement, Figure 1. Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. External validation with a larger sample size is warranted to facilitate personalization of PD-1/PD-L1 blockade for patients with NSCLC. Our website uses cookies to enhance your experience. A 2-tailed P < .05 was considered statistically significant. Please see our commenting policy for details. All Rights Reserved, Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine, United States Preventive Services Task Force, 2020;3(9):e2011818.  DT, Uram  RH, Ligon 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. The median (IQR) follow-up period among 67 patients who were censored was 20.5 (15.4-30.4) months. Conflict of Interest Disclosures: Dr Inui reported receiving grants from Chugai Pharmaceutical Co, Eli Lilly Japan, and MSD KK outside the submitted work. All Rights Reserved.  S, Okamoto Drafting of the manuscript: Inoue, Yoshimura, Inui, Karayama, Yasui, Hozumi, Suzuki, Furuhashi, Hashimoto, Inami, Sugimura, Suda.  MA. 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.  Y.  K, In this prospective study, we demonstrated that FISH-based PD-L1 amplification but not polysomy was associated with durable responses to nivolumab among patients with NSCLC. Residues forming the hydrophobic core are colored yellow.  Mutational landscape and sensitivity to immune checkpoint blockers. , Goodman  NI, 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 … Sequential nivolumab was given on day 1 of a 14-day cycle. 2017 Jul 13;60(13):5857-5867. doi: 10.1021/acs.jmedchem.7b00293. 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.  |  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%).  et al.  DL, Programmed cell death 1 ligand 1 (synonym CD274, B7 Homolog 1) ist ein Oberflächenprotein und beteiligt an der Hemmung der Immunantwort. Herbst It is … Statistical analysis: Inoue, Inui, Karayama, Yasui. Pretreatment tumor samples were collected for biomarker evaluation.  M, Lefebvre  CY, Keam Structure. 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). Supervision: Inui, Karayama, Hozumi, Suzuki, Enomoto, Sugimura, Suda. Adverse events were graded based on the National Cancer Institute Common Toxicity Criteria version 4.0.  KS, Lenkiewicz Customize your JAMA Network experience by selecting one or more topics from the list below. Validation Study of the E1L3N Anti–PD-L1 Antibody, eFigure 4.  H, Paz-Ares  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. , Sugimura  R, Ferrara  et al. Importance  OS was defined as the interval from the date of the first administration of nivolumab to the date of death from any cause. … Meaning  With the planned sample size, the ORR would be estimated with the half width of the 95% CI within 15%. Inoue Y, Yoshimura K, Nishimoto K, et al.  DT, Durham eCollection 2020 Oct 20. Data were analyzed from December 2019 to February 2020. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor.  A, Tay 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?  Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis. , Budczies (B) hPD-1 complexed with hPD-L1.  H, © 2020 American Medical Association. PD-L1 CNGs were identified in 32 patients (16.5%), including 5 (2.6%) with amplification and 27 (13.9%) with polysomy.  N, Hellmann We excluded patients with concomitant autoimmune diseases, interstitial lung diseases, uncontrolled symptomatic brain metastases, or other severe uncontrolled complications. Characteristics of Patients with PD-L1–Amplified Tumors. Copyright © 2015 Elsevier Ltd. All rights reserved.  K, Inoue  et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. 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. PD-L1 and CEP9 signals are shown in red and green, respectively. Programmed Cell Death Ligand-1 (PD-L1) and CD8 Expression Profiling Identify an Immunologic Subtype of Pancreatic Ductal Adenocarcinomas with Favorable Survival Ludmila …  Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via, Yoshimura 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 … 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. 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.  N, Havel 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. Here, we showed dysregulation of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1…  JN, Wang They were not compensated for their time. 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 … No other disclosures were reported. Targeting the programmed death-1 pathway in lymphoid neoplasms.  NA, Hellmann The 28-8 anti–PD-L1 antibody (Abcam) and FLAG-M2 monoclonal antibody (Sigma-Aldrich) were applied for the validation study. 2020 Oct 1;9(1):1818437. doi: 10.1080/2162402X.2020.1818437.  SJ, Gøtzsche Understanding the Targeting Mechanisms of Multi-Specific Biologics in Immunotherapy with Multiscale Modeling. (A) Apo-hPD-1. 2017 May 2;13(5):892-900. doi: 10.1039/c7mb00036g. 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. Epub 2017 Feb 11.  TA, Postow  Pembrolizumab versus chemotherapy for, Antonia  S, 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. 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. 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. Programmed cell death 1 (PD-1), a member of the B7 receptor family, is an inhibitory receptor expressed on the surface of T cells.  Nivolumab versus docetaxel in advanced squamous-cell non–small cell lung cancer. , Borghaei  B, Kim Close-Up Views of the hPD-1/hPD-L1 Interface, hPD-1 and hPD-L1 are represented by blue…, Figure 3. JAMA Netw Open. Conclusions and Relevance   MR, Monti This study was conducted in accordance with the Declaration of Helsinki26 and Good Clinical Practice Guidelines, and the protocol was approved by institutional review boards of all participating hospitals. Censoring was done at the date of last contact. 2016 May 24;7(21):30323-35. doi: 10.18632/oncotarget.8730. 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).  Cancer immunology: mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. , Tumeh  RS, Baas However, survival curves of duration of response overlapped between responders with PD-L1 TPS of at least 50% and those with PD-L1 TPS of less than 50% (eFigure 3B in the Supplement).  B, Andreozzi 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.  R, Chaput Figure 1. COVID-19 is an emerging, rapidly evolving situation. Kaumaya PTP, Guo L, Overholser J, Penichet ML, Bekaii-Saab T. Oncoimmunology.