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PD-L1 Cancer

Amir Salek Farrokhi, Narges Darabi, Bahman Yousefi, Rafee Habib Askandar, Mansoreh Shariati, Majid Eslami
Recent studies demonstrated that a combination of the gut microbiome has the vital effect on the efficacy of anticancer immune therapies. Regulatory effects of microbiota have been shown in different types of cancer therapies such as chemotherapy and immunotherapy. Immune-checkpoint-blocked therapies are the recent efficient cancer immunotherapy strategies. The target of immune-checkpoint blocking is cytotoxic T lymphocyte protein-4 (CTLA-4) or blockade of programmed death-1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) that they have been considered as cancer immunotherapy in recent years...
February 20, 2019: Journal of Cellular Physiology
Neal Ready, Matthew D Hellmann, Mark M Awad, Gregory A Otterson, Martin Gutierrez, Justin F Gainor, Hossein Borghaei, Jacques Jolivet, Leora Horn, Mihaela Mates, Julie Brahmer, Ian Rabinowitz, Pavan S Reddy, Jason Chesney, James Orcutt, David R Spigel, Martin Reck, Kenneth John O'Byrne, Luis Paz-Ares, Wenhua Hu, Kim Zerba, Xuemei Li, Brian Lestini, William J Geese, Joseph D Szustakowski, George Green, Han Chang, Suresh S Ramalingam
PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks...
February 20, 2019: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Arash Salmaninejad, Saeed Farajzadeh Valilou, Arezoo Gowhari Shabgah, Saeed Aslani, Malihe Alimardani, Alireza Pasdar, Amirhossein Sahebkar
Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells...
February 19, 2019: Journal of Cellular Physiology
Yijun Jia, Xuefei Li, Tao Jiang, Sha Zhao, Chao Zhao, Limin Zhang, Xiaozhen Liu, Jinpeng Shi, Meng Qiao, Jiawei Luo, Sangtian Liu, Ruoshuang Han, Chunxia Su, Shengxiang Ren, Caicun Zhou
Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment...
February 5, 2019: International Journal of Cancer. Journal International du Cancer
Mahtab Samimi
Merkel cell carcinoma (MCC) is an aggressive skin cancer. Until 2017, patients with advanced disease were typically treated with conventional chemotherapies, with a median response duration of 3 months. Increased evidence of the role of the immune system in controlling this cancer has paved the way for immune-based therapies, with programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors at the frontline. Avelumab, an anti-PD-L1 antibody, was the first-ever drug approved in advanced MCC after showing meaningful efficacy in a second-line setting...
February 19, 2019: American Journal of Clinical Dermatology
Vladimir N Ivanov, Jinhua Wu, Tony J C Wang, Tom K Hei
Despite advances in glioblastoma (GBM) therapy, prognosis of the disease remains poor with a low survival rate. Cannabidiol (CBD) can induce cell death and enhance radiosensitivity of GBM but not normal astrocytes. Inhibition of ATM kinase is an alternative mechanism for radiosensitization of cancer cells. In this study, we increased the cytotoxic effects of the combination of CBD and γ-irradiation in GBM cells through additional inhibition of ATM kinase with KU60019, a small molecule inhibitor of ATM kinase...
January 25, 2019: Oncotarget
Yuri Tolkach, Jörg Ellinger, Anika Kremer, Laura Esser, Stefan C Müller, Carsten Stephan, Klaus Jung, Marieta Toma, Glen Kristiansen, Stefan Hauser
BACKGROUND: The APLNR (apelin receptor) has been shown to be an essential gene for cancer immunotherapy, with deficiency in APLNR leading to immunotherapy failure. The aim of this study is to investigate the expression of APLN (apelin) and APLNR in patients with renal cell carcinoma (RCC), and its association with clinicopathological parameters and survival. METHODS: Three well-characterised patient cohorts with RCC were used: Study cohort 1 (clear-cell RCC; APLN/APLNR mRNA expression; n = 166); TCGA validation cohort (clear-cell RCC; APLN/APLNR mRNA expression; n = 481); Study cohort 2 (all RCC subtypes; APLNR protein expression/immunohistochemistry; n = 300)...
February 20, 2019: British Journal of Cancer
Cornelia Hutmacher, Nicolas Núñez, Anna Rita Liuzzi, Burkhard Becher, Dario Neri
Recombinant human interleukin-2 (IL2) is being considered as a combination partner for immune checkpoint inhibitors in cancer therapy, but the product only has a narrow therapeutic window. Therefore, we used F8-IL2, an antibody-IL2 fusion protein capable of selective localization to the tumor site, in combination with antibodies against murine CTLA-4, PD-1, and PD-L1. In immunocompetent mice bearing CT26 tumors, the combination of F8-IL2 with CTLA-4 blockade was efficacious, leading to increased progression-free survival and protective immunity against subsequent tumor re-challenges...
February 19, 2019: Cancer Immunology Research
Young Suk Lee, Eduardo Davila, Tianshu Zhang, Hugh P Milmoe, Stefanie N Vogel, Jonathan S Bromberg, Joseph R Scalea
Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin (ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1 tumor-bearing mice. MDSC development and function were assessed in vivo and in vitro with and without ATG administration. T cell suppression assays, RT-PCR, flow cytometry and arginase activity assays were used to assess MDSC phenotype and function...
January 2019: Innate Immunity
Marcelo V Negrao, Vincent K Lam, Alexandre Reuben, Maria Laura Rubin, Lara Lacerda Landry, Emily B Roarty, Waree Rinsurongkawong, Jeff Lewis, Jack A Roth, Stephen G Swisher, Don L Gibbons, Ignacio I Wistuba, Vassiliki Papadimitrakopoulou, Bonnie S Glisson, George R Blumenschein, J Jack Lee, John V Heymach, Jianjun Zhang
INTRODUCTION: Immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only ∼15% of patients achieve durable benefit. Understanding resistance mechanisms to ICB is pivotal in developing more effective treatment strategies. Recent studies showed human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of NSCLC patients treated with ICB...
February 16, 2019: Journal of Thoracic Oncology
Long Long, Chen Zhao, Muqimova Ozarina, Xianda Zhao, Jing Yang, Honglei Chen
Lung cancer is the most prevalent and deadly cancer worldwide. Immune checkpoint therapy, which targets regulatory pathways in T cells to boost anti-tumor immune response, has revolutionized lung cancer treatment paradigms. Inhibitors of the most established immune checkpoints such as programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) have been approved by the US Food and Drug Administration in the management of lung cancer. Despite the pronounced survival benefits that have been seen with immune checkpoint inhibitors, not all lung cancer patients respond to single-agent immunotherapy due to the complexity of the immune microenvironment and tumor resistance...
February 16, 2019: Clinical Drug Investigation
Kirstin Perdrizet, Natasha B Leighl
The treatment of advanced non-small cell lung cancer (NSCLC) has evolved to include targeted therapy, immunotherapy as well as chemotherapy for selected patients in the first-line setting. Angiogenesis inhibitors have been used in combination with chemotherapy in the first-line and maintenance settings providing improved progression-free survival (PFS) and objective response rate (ORR), as well as overall survival (OS) in selected studies. Biologic rationale exists for combining anti-angiogenic agents with immunotherapy and targeted kinase inhibitors (TKIs)...
February 18, 2019: Current Treatment Options in Oncology
Simona Sivori, Paola Vacca, Genny Del Zotto, Enrico Munari, Maria Cristina Mingari, Lorenzo Moretta
NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis. The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors. In humans, major activating receptors involved in target cell killing are the natural cytotoxicity receptors (NCRs) and NKG2D. Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress, viral infection, or tumor transformation. The HLA-class I-specific inhibitory receptors, including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E, constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells...
February 18, 2019: Cellular & Molecular Immunology
Triparna Sen, B Leticia Rodriguez, Limo Chen, Carminia Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S Glisson, Ignacio I Wistuba, Julien Sage, John V Heymach, Don L Gibbons, Lauren Averett Byers
Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB). Here, we show that targeting DNA damage response (DDR) proteins, poly ADP-ribose polymerase (PARP) and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the anti-tumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models...
February 18, 2019: Cancer Discovery
C Van Berckelaer, C Rypens, P van Dam, L Pouillon, M Parizel, K A Schats, M Kockx, W A A Tjalma, P Vermeulen, S van Laere, F Bertucci, C Colpaert, L Dirix
BACKGROUND: Inflammatory breast cancer (IBC) is a rare and rapidly progressive form of invasive breast cancer. The aim of this study was to explore the clinical evolution, stromal tumour-infiltrating lymphocytes (sTIL) infiltration and programmed death-ligand 1 (PD-L1) expression in a large IBC cohort. PATIENTS AND METHODS: Data were collected prospectively from patients with IBC as part of an international collaborative effort since 1996. In total, 143 patients with IBC starting treatment between June 1996 and December 2016 were included...
February 18, 2019: Breast Cancer Research: BCR
Xin Wang, Gaochao Guo, Hui Guan, Yang Yu, Jie Lu, Jinming Yu
PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells...
February 18, 2019: Journal of Experimental & Clinical Cancer Research: CR
Fang Wei, Tong Zhang, Shu-Chou Deng, Jian-Chang Wei, Ping Yang, Qiang Wang, Zhuan-Peng Chen, Wang-Lin Li, Hua-Cui Chen, He Hu, Jie Cao
PD-L1 is critical for tumor cell escape from immune surveillance by inhibiting T cell function via the PD-1 receptor. Accumulating evidence demonstrates that anti-PD-L1 monoclonal antibodies might potently enhance antitumor effects in various tumors, but the effect of PD-L1 on colorectal cancer stem cells (CSCs) remains unclear. We observed high PD-L1 expression in CD133+ CD44+ colorectal CSCs and CSC-enriched tumorspheres. Altering PD-L1 expression promoted colorectal CSC self-renewal by increasing the expression of stemness genes, the CD133+ CD44+ cell population sizes and the ability to form tumorspheres...
February 15, 2019: Cancer Letters
Pichaya Thanindratarn, Dylan C Dean, Scott D Nelson, Francis J Hornicek, Zhenfeng Duan
Bone sarcomas are a collection of sporadic malignancies of mesenchymal origin. The most common subtypes include osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. Despite the use of aggressive treatment protocols consisting of extensive surgical resection, chemotherapy, and radiotherapy, outcomes have not significantly improved over the past few decades for osteosarcoma or Ewing sarcoma patients. In addition, chondrosarcoma and chordoma are resistant to both chemotherapy and radiation therapy. There is, therefore, an urgent need to elucidate which novel new therapies may affect bone sarcomas...
April 2019: Journal of Bone Oncology
Sylvie Lantuejoul, Diane Damotte, Véronique Hofman, Julien Adam
Lung cancer is the leading cause of cancer death worldwide with low response rates to conventional chemotherapy. New promising therapies have emerged based on programmed cell death protein 1 (PD-1) immunity checkpoint inhibitors (ICI), including anti-PD-1, such as nivolumab and pembrolizumab, or programmed death ligand 1 (PD-L1) inhibitors, such as atezolizumab, durvalumab, and avelumab. The prescription of pembrolizumab has been approved by FDA and EMA for advanced stages non-small cell lung carcinoma (NSCLC), restricted for first-line setting to patients whose tumor presents ≥50% of PD-L1 positive tumor cells (TC), and ≥1% for second-line and beyond, leading to consider PD-L1 assay as a companion diagnostic tool for pembrolizumab...
January 2019: Journal of Thoracic Disease
Léa Berland, Simon Heeke, Olivier Humbert, Adam Macocco, Elodie Long-Mira, Sandra Lassalle, Virginie Lespinet-Fabre, Salomé Lalvée, Olivier Bordone, Charlotte Cohen, Sylvie Leroy, Véronique Hofman, Paul Hofman, Marius Ilié
In the last few years, the treatment of patients with non-small cell lung cancer (NSCLC) has impressively benefitted from immunotherapy, in particular from the inhibition of immune checkpoints such as programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). However, despite the significant survival benefit for some patients with advanced NSCLC, the objective response rates (ORRs) remain relatively low no more than 20-30% with a large proportion of patients demonstrating primary resistance...
January 2019: Journal of Thoracic Disease
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