Journal Articles

Checkpoint modulation

Cancer immunotherapeutic approaches that target stimulatory or inhibitory immune checkpoint pathways as well as immune related adverse events associated with these therapies

Engineering PD-1-Presenting Platelets for Cancer Immunotherapy

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Radical surgery still represents the treatment choice for several malignancies. However, local and distant tumor relapses remain the major causes of treatment failure, indicating that a postsurgery consolidation treatment is necessary. Immunotherapy with checkpoint inhibitors has elicited impressive clinical responses in several types of human malignancies and may represent the ideal consolidation treatment after surgery. Here, we genetically engineered platelets from megakaryocyte (MK) progenitor cells to express the programmed cell death protein 1 (PD-1). The PD-1 platelet and its derived microparticle could accumulate within the tumor surgical wound and revert exhausted CD8(+) T cells, leading to the eradication of residual tumor cells. Furthermore, when a low dose of cyclophosphamide (CP) was loaded into PD-1-expressing platelets to deplete regulatory T cells (Tregs), an increased frequency of reinvigorated CD8(+) lymphocyte cells was observed within the postsurgery tumor microenvironment, directly preventing tumor relapse.

Author Info: (1) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University

Author Info: (1) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University , Shenzhen 518060 , China. Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (2) Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (3) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (4) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (5) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (6) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (7) Lineberger Comprehensive Cancer Center , University of North Carolina , Chapel Hill , North Carolina 27599 , United States. (8) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University , Shenzhen 518060 , China. (9) Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States.

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Glyco-Engineered Anti-Human Programmed Death-Ligand 1 Antibody Mediates Stronger CD8 T Cell Activation Than Its Normal Glycosylated and Non-Glycosylated Counterparts

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The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a central role in suppression of anti-tumor immunity. Blocking the axis by targeting PD-L1 with monoclonal antibodies is an effective and already clinically approved approach to treat cancer patients. Glyco-engineering technology can be used to optimize different properties of monoclonal antibodies, for example, binding to FcgammaRs. We generated two glycosylation variants of the same anti-PD-L1 antibody: one bearing core fucosylated N-glycans in its Fc part (92%) and its de-fucosylated counterpart (4%). The two glycosylation variants were compared to a non-glycosylated commercially available anti-PD-L1 antibody in various assays. No differences were observed regarding binding to PD-L1 and blocking of this interaction with its counter receptors PD-1 or CD80. The de-fucosylated anti-PD-L1 antibody showed increased FcgammaRIIIa binding resulting in enhanced antibody dependent cellular cytotoxicity (ADCC) activity against PD-L1(+) cancer cells compared to the "normal"-glycosylated variant. Both glycosylation variants showed no antibody-mediated lysis of B cells and monocytes. The non-glycosylated reference antibody showed no FcgammaRIIIa engagement and no ADCC activity. Using mixed leukocyte reaction it was observed that the de-fucosylated anti-PD-L1 antibody induced the strongest CD8 T cell activation determined by expression of activation markers, proliferation, and cytotoxicity against cancer cells. The systematic comparison of anti-PD-L1 antibody glycosylation variants with different Fc-mediated potencies demonstrates that our glyco-optimization approach has the potential to enhance CD8 T cell-mediated anti-tumor activity which may improve the therapeutic benefit of anti-PD-L1 antibodies.

Author Info: (1) Glycotope GmbH, Berlin, Germany. (2) Glycotope GmbH, Berlin, Germany. (3) Glycotope GmbH, Berlin, Germany. (4) Glycotope GmbH, Berlin, Germany. (5) Glycotope GmbH, Berlin, Germany

Author Info: (1) Glycotope GmbH, Berlin, Germany. (2) Glycotope GmbH, Berlin, Germany. (3) Glycotope GmbH, Berlin, Germany. (4) Glycotope GmbH, Berlin, Germany. (5) Glycotope GmbH, Berlin, Germany. (6) Glycotope GmbH, Berlin, Germany. (7) Glycotope GmbH, Berlin, Germany.

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A PKPD analysis of circulating biomarkers and their relationship to tumor response in atezolizumab-treated non-small cell lung cancer patients

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To assess circulating biomarkers as predictors of anti-tumor response to atezolizumab (anti-PD-L1, Tecentriq), serum PK and 95 plasma biomarkers were analyzed in 88 relapsed/refractory non-small cell lung cancer (NSCLC) patients receiving atezolizumab IV q3w (10-20 mg/kg) in the PCD4989g Phase 1 clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a PKPD tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with AUC, baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin 18 level from baseline at day 21 (RCFBIL-18,d21 ). While AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL-18,d21 appeared relevant to the duration of the response. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden. Pharmetheus AB, Uppsala, Sweden. (2) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (3)

Author Info: (1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden. Pharmetheus AB, Uppsala, Sweden. (2) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (3) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (4) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (5) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (6) Department of Clinical Pharmacology, Genentech,1 DNA Way, South San Francisco, USA. (7) Pharmetheus AB, Uppsala, Sweden. (8) Department of Pharmaceutical Biosciences, Uppsala University, Sweden. Pharmetheus AB, Uppsala, Sweden.

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Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Summarized Overview

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BACKGROUND: The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunmodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin. OBJECTIVE: To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management. METHOD: English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review. RESULTS: The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported. CONCLUSION: Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment, so that permanent discontinuation of therapy is not commonly necessary. In the case of life threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

Author Info: (1) Dermatology Department, University General Hospital of Patras. Greece. (2) Dermatology Department, University General Hospital of Patras. Greece. (3) Dermatology Department, University General Hospital of Patras. Greece.

Author Info: (1) Dermatology Department, University General Hospital of Patras. Greece. (2) Dermatology Department, University General Hospital of Patras. Greece. (3) Dermatology Department, University General Hospital of Patras. Greece.

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Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

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The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB.

Author Info: (1) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (2) Fiona Elsey Cancer

Author Info: (1) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (2) Fiona Elsey Cancer Research Institute, Ballarat, VIC, Australia. (3) Department of Medicine, University of Alberta, Edmonton, AB, Canada. (4) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (5) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (6) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (7) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia. (8) Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.

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Cancer Stem Cell Vaccination With PD-L1 and CTLA-4 Blockades Enhances the Eradication of Melanoma Stem Cells in a Mouse Tumor Model

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Immune checkpoint inhibitors and monoclonal antibodies reinvigorate cancer immunotherapy. However, these immunotherapies only benefit a subset of patients. We previously reported that ALDH tumor cells were highly enriched for cancer stem cells (CSCs), and ALDH CSC lysate-pulsed dendritic cell (CSC-DC) vaccine was shown to induce CSC-specific cytotoxic T lymphocytes. In this study, we investigated the CSC targeting effect of the CSC-DC vaccine combined with a dual blockade of programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein (CTLA-4) in B16-F10 murine melanoma tumor model. Our data showed that animals treated with the dual blockade of programmed death-ligand 1 and CTLA-4 and CSC-DC vaccine conferred significantly more tumor regression than the CSC-DC vaccine alone. Importantly, the triple combination treatment dramatically eliminated ALDH CSCs in vivo. We observed that CSC-DC vaccine in combination with anti-PD-L1 and anti-CTLA-4 administration resulted in approximately 1.7-fold fewer PD-1CD8 T cells and approximately 2.5-fold fewer CTLA-4CD8 T cells than the populations observed following the CSC-DC vaccination alone. Moreover, significant antitumor effects and dramatically eliminated ALDH CSCs following the triple combination treatment were accompanied by significantly enhanced T-cell expansion, suppressed transforming growth factor beta secretion, enhanced IFN-gamma secretion, and significantly enhanced host specific CD8 T-cell response against CSCs. Collectively, these data showed that administration of a-PD-L1 and a-CTLA-4 combined with CSC-DC vaccine may represent an effective immunotherapeutic strategy for cancer patients in clinical.

Author Info: (1) Department of Pediatrics. (2) Department of Geriatrics, Renmin Hospitial of Wuhan University, Wuhan. (3) Department of Hematology. (4) The Clinical Trial Institute, Peking University

Author Info: (1) Department of Pediatrics. (2) Department of Geriatrics, Renmin Hospitial of Wuhan University, Wuhan. (3) Department of Hematology. (4) The Clinical Trial Institute, Peking University Shenzhen Hospital, Shenzhen. (5) Department of Pediatrics. (6) Department of Pediatrics. (7) Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. (8) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. (9) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. (10) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.

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PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells

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CD4(+) T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3(+) Th1 cells (denoted as Tbet(+)iTregPDL1 cells) and inducible regulatory T (iTreg) cells. Tbet(+)iTregPDL1 cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to Tbet(+)iTregPDL1 cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in Tbet(+)iTreg cells. Also, Aep(-/-) iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1-mediated Foxp3 maintenance in Tbet(+) Th1 cells occurred both in tumor infiltrating lymphocytes (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.

Author Info: (1) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (2) Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH

Author Info: (1) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (2) Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (3) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (4) Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (5) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (6) Biological Mass Spectrometry Core, University of Manchester, Manchester M13 9PL, UK. (7) Flow Cytometry Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA. (8) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. (9) School of Medicine, Stanford University, Stanford, CA 94305, USA. (10) Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (11) Division of Veterinary Resources, Office of Research Services, NIH, Bethesda, MD 20892, USA. (12) School of Medicine, Stanford University, Stanford, CA 94305, USA; Drug Discovery Biology, Monash University, Melbourne, VIC 3800, Australia. (13) College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK. (14) Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (15) Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (16) Leiden Institute of Chemistry and Institute of Chemical Immunology, Leiden University, 2311 EZ Leiden, the Netherlands. (17) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Translational Gastroenterology Unit, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DU, UK; Department of Haematology, Northern Centre for Cancer Care, Newcastle upon Tyne NE2 4HH, UK. (18) School of Medicine, Stanford University, Stanford, CA 94305, USA. (19) College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK. (20) Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. (21) Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: shoba.amarnath@newcastle.ac.uk.

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Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study

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INTRODUCTION: The utility of immunotherapy in elderly melanoma patients is debated. We aimed in this study to evaluate the efficacy and tolerability of immunotherapy among elderly patients. METHOD: This is a retrospective single-institution cohort study. Patients aged 75 years and above who had been treated with nivolumab, pembrolizumab or ipilimumab for advanced or metastatic melanoma, were included. Patients and disease characteristics were collected using electronic medical records. Objective response was determined according to the immune-related response criteria. Drug-related toxicities (DRT) were graded according to the CTCAE v4.03. RESULTS: 99 patients were included with a mean age of 80 years (SD = 4). One patient received nivolumab and ipilimumab combination, but died because of drug-related diverticulitis. Median PFS on pembrolizumab, nivolumab or ipilimumab were equal to 11.9 (95% CI 5.4-18.4), 1.4 (95% CI 0.01-2.8), and 2.8 months (95% CI 2.6-3), respectively, while objective response rates were equal to 51.6, 12.5, and 17.3%, respectively. Median OS was not reached in patients who received only pembrolizumab, 8.7 months in the ipilimumab only group, and 23 months in patients receiving several immune therapies sequentially. Pembrolizumab, nivolumab, and ipilimumab grade 3-4 DRT rates were equal to 24.2, 62.5, and 32.7% respectively, while discontinuation rates were equal to 43.5, 62.5, and 28.8%, respectively. CONCLUSIONS: Our study suggests that immunotherapy is effective and well tolerated in the elderly. The PFS on pembrolizumab was greater than expected, a finding that needs to be investigated further.

Author Info: (1) Department of Medical Oncology, Gustave Roussy Institut, 114 Rue Edouard Vaillant, 94800, Villejuif, France. tony.ibrahim@gustaveroussy.fr. (2) Dermatology Department, Gustave Roussy Institut, Villejuif, France. (3)

Author Info: (1) Department of Medical Oncology, Gustave Roussy Institut, 114 Rue Edouard Vaillant, 94800, Villejuif, France. tony.ibrahim@gustaveroussy.fr. (2) Dermatology Department, Gustave Roussy Institut, Villejuif, France. (3) Faculty of Medicine, Saint Joseph University, Beirut, Lebanon. (4) Dermatology Department, Gustave Roussy Institut, Villejuif, France.

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Strong PD-L1 expression predicts poor response and de novo resistance to EGFR TKIs among non-small cell lung cancer patients with EGFR mutation

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INTRODUCTION: This study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. METHODS: We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated. RESULTS: Among the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate (ORR), compared with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002), and shortened progression-free survival (PFS, 3.8 vs 6.0 vs 9.5 months, P<0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, we found a high proportion of PD-L1 and CD8 dual-positive cases among patients with de novo resistance (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-PD-1 therapy. CONCLUSION: This study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to PD-1 blockade.

Author Info: (1) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (2) Department of Radiation

Author Info: (1) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (2) Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China. (3) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (4) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (5) Department of Pathology and Laboratory Medicine, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (6) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (7) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (8) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (9) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (10) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (11) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (12) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (13) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (14) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (15) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (16) Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. (17) Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address: syylwu@live.cn.

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Mismatch repair protein defects and microsatellite instability in malignant pleural mesothelioma

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INTRODUCTION: Malignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-PD-1 therapy, however it appears to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumour mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centres have adopted IHC to screen for MSI-high colorectal cancers. We profiled a large mesothelioma cohort to determine the rate of negative immunohistochemistry for the four common mismatch repair proteins. DESIGN: A tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. Immunohistochemistry (IHC) for the four common mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6) was performed. PD-L1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analysed for microsatellite instability using the Promega MSI Analysis System, Version 1.2. RESULTS: Of 335 patients profiled, 329 had intact mismatch repair proteins by immunohistochemistry. Six samples with absent mismatch repair protein immunohistochemistry analysis were analysed for MSI and confirmed to be negative. Of the six IHC+ samples, five were absent for PD-L1 staining and one sample had more than 5% staining. CONCLUSION: In this large retrospective series, we were unable to identify any malignant pleural mesothelioma patients with microsatellite instability. Response to anti-PD-1 based immunotherapy may be driven by other mechanisms.

Author Info: (1) Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. (2) Cancer Immuno-Biology

Author Info: (1) Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. (2) Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia. (3) Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. (4) Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. (5) School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. (6) School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. (7) Cancer Immuno-Biology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia; Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Heidelberg, Victoria, Australia. Electronic address: Tom.John@onjcri.org.au.

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