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pd-l1, lung cancer

Ettore D'Argento, Sabrina Rossi, Giovanni Schinzari, Antonia Strippoli, Michele Basso, Alessandra Cassano, Carlo Barone
New treatments-as immunotherapies and new antiangiogenic agents-are now available in second-line setting for patients affected by EGFR wild-type and ALK-negative non-small-cell lung cancer (NSCLC). Nintedanib, ramucirumab, nivolumab and pembrolizumab have to be included in the therapeutic sequences for patients affected by NSCLC, but no clear selection criteria are to date offered, except for patients with PD-L1 expression ≥50 %. Performance status, smoking habits and comorbidities should be considered as clinical criteria in order to select the appropriate treatment, but also tumour characteristics as histotype, platinum resistance and rapid progression after a first-line therapy should be taken into account...
December 2016: Current Treatment Options in Oncology
David J Pinato, Robert J Shiner, Solomon D T White, James R M Black, Pritesh Trivedi, Justin Stebbing, Rohini Sharma, Francesco A Mauri
Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray...
2016: Oncoimmunology
Elisabet Cuyàs, Almudena Pérez-Sánchez, Vicente Micol, Javier A Menendez, Joaquim Bosch-Barrera
The signal transducer and activator of transcription 3 (STAT3) has been suggested to play a prominent role in mediating non-small-cell lung cancer (NSCLC) resistance to some tyrosine kinase inhibitor (TKI)-mediated therapies. Using a model of anaplastic lymphoma kinase gene (ALK)-translocated NSCLC with acquired resistance to the ALK TKI crizotinib, but lacking amplifications or mutations in the kinase domain of ALK, we herein present evidence that STAT3 activation is a novel mechanism of crizotinib resistance that involves the upregulation of immune escape and epithelial to mesenchymal transition (EMT) signaling pathways...
October 18, 2016: Cell Cycle
Gustavo Dix Junqueira Pinto, Luciano de Souza Viana, Cristovam Scapulatempo Neto, Sérgio Vicente Serrano
Lung cancer is the leading world cause of cancer-related death, in both genders, and smoking is the main etiological factor. The discovery of immune checkpoints corroborates the hypothesis that ligands presented in tumors modulate the mechanisms of carcinogenesis and the immune activity of tumor microenvironment. Among the most studied coregulatory molecules, PD-1 (programmed cell death 1) and its ligand PD-L1 (programmed cell death 1 ligand 1) are noteworthy. The present study aims to enhance the understanding of the tumor microenvironment of lung cancer patients who underwent surgery, by means of analysis of PD-L1 expression in tumor cells and in intratumoral immune cells (IICs)...
2016: Journal of Immunology Research
Corey J Langer, Shirish M Gadgeel, Hossein Borghaei, Vassiliki A Papadimitrakopoulou, Amita Patnaik, Steven F Powell, Ryan D Gentzler, Renato G Martins, James P Stevenson, Shadia I Jalal, Amit Panwalkar, James Chih-Hsin Yang, Matthew Gubens, Lecia V Sequist, Mark M Awad, Joseph Fiore, Yang Ge, Harry Raftopoulos, Leena Gandhi
BACKGROUND: Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC...
October 10, 2016: Lancet Oncology
Jung-Jyh Hung, Shiu-Feng Huang, Ying-Ying Shen, Yu-Chung Wu, Teh-Ying Chou, Wen-Hu Hsu
BACKGROUND: The programmed cell death-ligand 1 (PD-L1) pathway plays an important role in maintaining immune homeostasis. The PD-L1 pathway may also protect tumors from attack by cytotoxic T cells. Blockade of programmed cell death 1 (PD1) or PD-L1 induced durable tumor regression in patients with advanced cancers, including non-small cell lung cancer (NSCLC). However, the prognostic value of PD-L1 expression in patients with lung adenocarcinoma remains controversial. METHODS: A total of 112 patients with resected lung adenocarcinoma were included in the study...
October 12, 2016: Annals of Thoracic Surgery
Manish K Thakur, Shirish M Gadgeel
Therapy of non-small cell lung cancer (NSCLC) patients has evolved over the past few years with the incorporation of targeted therapy and immune therapy. These changes have increased the importance of prognostic and predictive biomarkers to enable practicing physicians in making the most appropriate treatment decisions for NSCLC patients. A variety of prognostic factors based on clinical and pathologic features determine the overall outcome of the patient and these factors do influence decisions regarding initiation of therapy...
October 2016: Seminars in Respiratory and Critical Care Medicine
Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Rie Sakakibara, Hironori Ninomiya, Sophia Subat, Hiroko Nagano, Kimie Nomura, Sakae Okumura, Tomoko Shibutani, Yuichi Ishikawa
OBJECTIVES: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients...
October 1, 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O'Brien, Suman Rao, Katsuyuki Hotta, Melanie A Leiby, Gregory M Lubiniecki, Yue Shentu, Reshma Rangwala, Julie R Brahmer
Background Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). Methods In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy...
October 8, 2016: New England Journal of Medicine
Marlon C Rebelatto, Anita Midha, Amita Mistry, Constantine Sabalos, Nicole Schechter, Xia Li, Xiaoping Jin, Keith E Steele, Paul B Robbins, John A Blake-Haskins, Jill Walker
BACKGROUND: A high-quality programmed cell-death ligand 1 (PD-L1) diagnostic assay may help predict which patients are more likely to respond to anti-programmed cell death-1 (PD-1)/PD-L1 antibody-based cancer therapy. Here we describe a PD-L1 immunohistochemical (IHC) staining protocol developed by Ventana Medical Systems Inc. and key analytical parameters of its use in formalin-fixed, paraffin-embedded (FFPE) samples of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC)...
October 8, 2016: Diagnostic Pathology
Jiaxing Huang, Yaxiong Zhang, Jin Sheng, Hongyu Zhang, Wenfeng Fang, Jianhua Zhan, Ting Zhou, Ying Chen, Lin Liu, Li Zhang
BACKGROUND: Nivolumab (BMS-936558/ONO-4538) was the first monoclonal antibody targeting programmed death (PD)-1. So far, a number of clinical trials on nivolumab have showed satisfactory efficacy in treating non-small-cell lung cancer (NSCLC). Herein, we present a meta-analysis evaluating the efficacy and safety of nivolumab for previously treated advanced NSCLC patients. METHODS: Electronic databases were searched for eligible literature. Data of objective response rate (ORR), disease control rate, overall survival, progression-free survival, and adverse effects (AEs) were extracted and pooled...
2016: OncoTargets and Therapy
Pankit Vachhani, Hongbin Chen
Immunotherapy with immune checkpoint inhibitors has opened a new arena in cancer therapeutics. Pembrolizumab is a highly selective anti-programmed cell death protein 1 (PD-1) antibody that has shown efficacy, leading to survival benefit and durable responses, in some patients with non-small cell lung cancer (NSCLC). It has been approved by the US Food and Drug Administration for the treatment of patients with metastatic NSCLC, whose tumors express PD-1 ligand 1 (PD-L1), with disease progression on or after platinum-containing chemotherapy...
2016: OncoTargets and Therapy
Grit S Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y Li, Kevin A Buczkowski, Aaron K Grant, Soumya Ullas, Kevin Rhee, Jillian D Cavanaugh, Neermala Poudel Neupane, Camilla L Christensen, Jan M Herter, G Mike Makrigiorgos, F Stephen Hodi, Gordon J Freeman, Glenn Dranoff, Peter S Hammerman, Alec C Kimmelman, Kwok-Kin Wong
Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional Kras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1)...
June 16, 2016: JCI Insight
Patrick H Lizotte, Elena V Ivanova, Mark M Awad, Robert E Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S Herter-Sprie, Abigail Santos, Nora B Feeney, Cloud P Paweletz, Meghana M Kulkarni, Adam J Bass, Anil K Rustgi, Guo-Cheng Yuan, Donald W Kufe, Pasi A Jänne, Peter S Hammerman, Lynette M Sholl, F Stephen Hodi, William G Richards, Raphael Bueno, Jessie M English, Mark A Bittinger, Kwok-Kin Wong
BACKGROUND. Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. METHODS. We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC)...
September 8, 2016: JCI Insight
Sherif Abdelhamed, Keisuke Ogura, Satoru Yokoyama, Ikuo Saiki, Yoshihiro Hayakawa
While cancer development and progression can be controlled by cytotoxic T cells, it is also known that tumor-specific CD8(+)T cells become functionally impaired by acquiring a group of inhibitory receptors known as immune checkpoints. Amongst those, programmed death-1 (PD-1) is one of the most recognized negative regulators of T cell function. In non-small lung cancers (NSCLCs), the aberrant activation of epidermal growth factor receptor (EGFR) is known to induce PD-L1 expression and further the treatment with gefitinib, a tyrosine kinase inhibitor (TKI) for EGFR, decrease the expression of PD-L1 on NSCLC...
2016: Journal of Cancer
Xue Pan, Anyuan Zhong, Yufei Xing, Minhua Shi, Bin Qian, Tong Zhou, Yongjing Chen, Xueguang Zhang
Soluble and membrane-bound programmed death ligand-1 (sPD-L1 and mPD-L1, respectively) have been demonstrated to participate in the immune suppression of non-small cell lung cancer. However, the contribution of sPD-L1 and mPD-L1 to immune regulation and disease progression in patients with pleural effusions remains unknown. The present study evaluated the levels of sPD-L1 and membrane-bound PD-1/PD-L1 in the peripheral blood and pleural effusions of patients with tuberculous pleural effusion (TPE), malignant pleural effusion (MPE) and non-tuberculous non-malignant pleural effusion (n-TB n-M)...
October 2016: Experimental and Therapeutic Medicine
Yuh-Min Chen
Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed cell death protein 1 (PD-1) pathway [PD-1/programmed death-ligand 1 (PD-L1)] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups...
September 29, 2016: Journal of the Chinese Medical Association: JCMA
Paul Zarogoulidis, Savvas Petanidis, Kalliopi Domvri, Efrosini Kioseoglou, Doxakis Anestakis, Lutz Freitag, Konstantinos Zarogoulidis, Wolfgang Hohenforst-Schmidt, Wilfried Eberhardt
Chemoresistance is a major challenge in lung cancer treatment. Recent findings have revealed that autophagic mechanism contributes significantly to immunosuppressive related chemoresistance. For that reason, targeting autophagy-related immunosuppression is an important approach to reverse tumor drug resistance. In this study, we report for the first time that autophagy inhibition triggers upregulation of CD4(+), Foxp3(+) tumor infiltrating lymphocytes in late metastatic lung cancer tissues. Furthermore, autophagy blockage induces chemosensitization to carboplatin, immune activation and cell cycle arrest...
September 16, 2016: Molecular Oncology
H Kadara, M Choi, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, Y Yoo, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Lee, R P Lifton, I I Wistuba, R S Herbst
BACKGROUND: Lung adenocarcinomas (LUADs) lead to the majority of deaths attributable to lung cancer. We performed whole-exome sequencing (WES) and immune profiling analyses of a unique set of clinically annotated early-stage LUADs to better understand the pathogenesis of this disease and identify clinically relevant molecular markers. METHODS: We performed WES of 108 paired stage I-III LUADs and normal lung tissues using the Illumina HiSeq 2000 platform. Ten immune markers (PD-L1, PD-1, CD3, CD4, CD8, CD45ro, CD57, CD68, FOXP3 and Granzyme B) were profiled by imaging-based immunohistochemistry in a subset of LUADs (n=92)...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
M Choi, H Kadara, J Zhang, E P Cuentas, J R Canales, S G Gaffney, Z Zhao, C Behrens, J Fujimoto, C Chow, K Kim, N Kalhor, C Moran, D Rimm, S Swisher, D L Gibbons, J Heymach, E Kaftan, J P Townsend, T J Lynch, J Schlessinger, J Jack Lee, R P Lifton, R S Herbst, I I Wistuba
BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for 20-30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. METHODS: Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n=108) were analyzed by WES...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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