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PD-L1 Cancer

Moshe C Ornstein, Jorge A Garcia
Background: Checkpoint inhibitors (CPI) have now been established as standard agents in the management of patients with metastatic renal cell carcinoma (mRCC). Given the unique toxicity profiles of CPIs, a detailed understanding of their incidence rate and characteristics is critical. Objective: To perform a systematic review for the analysis of the incidence rate and characteristics of toxicities in mRCC patients treated with CPIs in published clinical trials. Methods: A systematic search of EMBASE (Ovid) and MEDLINE (Ovid) was conducted as per PRISMA guidelines to identify prospective clinical trials of checkpoint inhibitors in mRCC...
November 27, 2017: Kidney cancer
Naoki Takasaka, Robert I Seed, Anthony Cormier, Andrew J Bondesson, Jianlong Lou, Ahmed Elattma, Saburo Ito, Haruhiko Yanagisawa, Mitsuo Hashimoto, Royce Ma, Michelle D Levine, Jean Publicover, Rashaun Potts, Jillian M Jespersen, Melody G Campbell, Fraser Conrad, James D Marks, Yifan Cheng, Jody L Baron, Stephen L Nishimura
TGF-β is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-β (L-TGF-β) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-β. Binding of L-TGF-β to integrin αvβ8 results in activation of TGF-β. We engineered and used αvβ8 antibodies optimized for blocking or detection, which - respectively - inhibit tumor growth in syngeneic tumor models or sensitively and specifically detect β8 in human tumors...
October 18, 2018: JCI Insight
Uffe Klausen, Staffan Holmberg, Morten Orebo Holmström, Nicolai Grønne Dahlager Jørgensen, Jacob Handlos Grauslund, Inge Marie Svane, Mads Hald Andersen
Peptides vaccination is an interesting approach to activate T-cells toward desired antigens in hematological malignancies. In addition to classical tumor associated antigens, such as cancer testis antigens, new potential targets for peptide vaccination comprise neo-antigens including JAK2 and CALR mutations, and antigens from immune regulatory proteins in the tumor microenvironment such as programmed death 1 ligands (PD-L1 and PD-L2). Immunosuppressive defenses of tumors are an important challenge to overcome and the T cell suppressive ligands PD-L1 and PD-L2 are often present in tumor microenvironments...
2018: Frontiers in Immunology
Xingliang Guo, Hua Jiang, Bizhi Shi, Min Zhou, Honghong Zhang, Zhimin Shi, Guoxiu Du, Hong Luo, Xiuqi Wu, Yi Wang, Ruixin Sun, Zonghai Li
Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system...
2018: Frontiers in Pharmacology
Viswanath Gunda, Benjamin Gigliotti, Dorothy Ndishabandi, Tameem Ashry, Michael McCarthy, Zhiheng Zhou, Salma Amin, Gordon J Freeman, Alessandro Alessandrini, Sareh Parangi
BACKGROUND: Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite aggressive multimodal therapy. ATC has a high prevalence of BRAFV600E mutations and is associated with an immunosuppressive microenvironment; we previously demonstrated that the combination of BRAF inhibitor and checkpoint inhibitor immunotherapy synergistically reduce tumour volume in an immunocompetent mouse model of orthotopic ATC. METHODS: We again utilised our mouse model of ATC to assess the combination of BRAFV600E inhibitor PLX4720 and anti-PD-L1 or anti-PD-1 antibody on survival, and performed immune cell profiling of lymphoid and myeloid-lineage cells during maximal treatment response and tumour regrowth...
October 17, 2018: British Journal of Cancer
Dass S Vinay, Byoung S Kwon
Immunomodulatory antibodies that directly trigger and reawaken suppressed T-cell effector function are termed 'checkpoint inhibitors'. CTLA-4 and PD-1/PD-L1 molecules are the most studied inhibitory immune check points against cancer and because of this therapeutic property have entered the clinic for treating a variety of tumor types. The results so far demonstrate a positive impact on cancer remission. Preclinical studies have demonstrated that targeting a number of other T-cell surface molecules including both positive and negative immune regulators, also possesses strong antitumor activity...
October 2018: Immunotherapy
Liannv Qiu, Qinhua Yu, Yonglie Zhou, Sujie Zheng, Jiaojiao Tao, Qian Jiang, Guorong Yuan
Non-small cell lung cancer (NSCLC) represents one of the most common and aggressive cancers worldwide, as it typically displays irreversible progression and poor prognosis. The interaction between programmed cell death 1 (PD-1) and its ligand, PD-L1, plays important roles in tumor immunology. Follicular helper T (Tfh) cells have characteristically high PD-1 expression; thus, in the present study, we investigated the role of circulating Tfh cells and their correlation with disease-free survival after tumor resection in NSCLC...
October 16, 2018: Cancer Science
Lukanxuan Wu, Chunzi Lv, Yifeng Su, Chunyan Li, Hui Zhang, Xinbo Zhao, Mingjiang Li
The programmed death-1 (PD-1)/PD-L1 pathway plays important roles in immune responses and peripheral tolerance. Under pathological conditions, this pathway can suppress protective T cell responses and induce immune system disorders. Endometriosis (EM) is an estrogen-dependent, immune-associated disease. The expression of PD-1 and PD-L1 has been studied in a variety of cancers and autoimmune diseases. Few studies, however, have attempted to explore their expression and the possibility that they are regulated by estrogen in EM...
October 16, 2018: Gynecological Endocrinology
Bin Shao, Chia-Wei Li, Seung-Oe Lim, Linlin Sun, Yun-Ju Lai, Junwei Hou, Chunxiao Liu, Chiung-Wen Chang, Yufan Qiu, Jung-Mao Hsu, Li-Chuan Chan, Zhengyu Zha, Huiping Li, Mien-Chie Hung
Triple-negative breast cancer (TNBC), the most difficult-to-treat breast cancer subtype, lacks well-defined molecular targets. TNBC has increased programmed death-ligand 1 (PD-L1) expression, and its immunosuppressive nature makes it suitable for immune checkpoint blockade therapy. However, the response rate of TNBC to anti-PD-L1 or anti-programmed cell death protein 1 (PD-1) therapy remains unsatisfactory, as only 10-20% of TNBC patients have a partial response. Glycosylated PD-L1, the functional form of PD-L1, is required for PD-L1-PD-1 interaction...
2018: American Journal of Cancer Research
Qiao Yang, Zihan Xu, Linpeng Zheng, Luping Zhang, Qiai You, Jianguo Sun
Immune checkpoint inhibitor (ICI) therapy had achieved significant clinical benefit in multiple malignant solid tumors, such as non-small cell lung cancer, melanoma and urothelial cancer. ICI therapy not only revolutionarily altered the treatment strategy of malignant solid tumors, but also dramatically prolonged overall survival. However, the objective response rate (ORR) of ICI therapy in second line treatment remains 20% or less. How to find patients eligible for ICI therapy by effective biomarkers became hot nowadays...
2018: American Journal of Cancer Research
Massimiliano Salati, Cinzia Baldessari, Fiorella Calabrese, Giulio Rossi, Elisa Pettorelli, Giulia Grizzi, Massimo Dominici, Fausto Barbieri
Background: Pulmonary sarcomatoid carcinoma is a rare, poorly differentiated, and highly aggressive type of non-small cell lung cancer. High tumor mutational burden and PD-L1 overexpression make it an excellent candidate for immunotherapy. Objectives and Method: We presented the case of a patient who underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for an infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV pulmonary sarcomatoid carcinoma...
September 2018: Case Reports in Oncology
Rutika Mehta, Anand Shah, Khaldoun Almhanna
Gastric and esopahgeal cancers account for the six most common causes of cancer death worldwide. Locally advanced resectable cancers have a 5-year life expectancy of 30%. Despite use of chemotherapy, median overall survival for stage IV cancer rarely exceeds 1 year. A subset of gastric cancers such as microsatellite-instable tumor and Epstein-Barr virus-positive tumors have a rich immune infiltrate that makes them more responsive to immune-directed therapies. Tumors can evade T-cell-mediated "immune surveillance" by activating the programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway...
2018: OncoTargets and Therapy
Steve Seung-Young Lee, Vytautas P Bindokas, Stephen J Kron
Macromolecular cancer drugs such as therapeutic antibodies and nanoparticles are well known to display slow extravasation and incomplete penetration into tumors, potentially protecting cancer cells from therapeutic effects. Conventional assays to track macromolecular drug delivery are poorly matched to the heterogeneous tumor microenvironment, but recent progress on optical tissue clearing and three-dimensional (3D) tumor imaging offers a path to quantitative assays with cellular resolution. Here, we apply Transparent Tissue Tomography (T3) as a tool to track perfusion and delivery in the tumor and to evaluate target binding and vascular permeability...
October 15, 2018: Molecular Cancer Therapeutics
Shuang G Zhao, Jonathan Lehrer, S Laura Chang, Rajdeep Das, Nicholas Erho, Yang Liu, Martin Sjöström, Robert B Den, Stephen J Freedland, Eric A Klein, R Jeffrey Karnes, Edward M Schaeffer, Melody Xu, Corey Speers, Paul L Nguyen, Ashley E Ross, June M Chan, Matthew R Cooperberg, Peter R Carroll, Elai Davicioni, Lawrence Fong, Daniel E Spratt, Felix Y Feng
Background: Immunotherapy has been less successful in treating prostate cancer than other solid tumors. We sought to better understand the immune landscape in prostate cancer and identify immune-related biomarkers and potential therapeutic targets. Methods: We analyzed gene expression data from 7826 prospectively collected prostatectomy samples (2013-2016), and 1567 retrospective samples with long-term clinical outcomes, for a total of 9393 samples, all profiled on the same commercial clinical platform in a CLIA-certified lab...
October 13, 2018: Journal of the National Cancer Institute
Marius Ilié, Mélanie Ngo-Mai, Elodie Long-Mira, Sandra Lassalle, Catherine Butori, Coraline Bence, Marame Hamila, Véronique Hofman, Paul Hofman
Pembrolizumab monotherapy has been approved for the first- and second-line treatment of patients with PD-L1-expressing advanced non-small cell lung cancer (NSCLC). Testing for PD-L1 expression with the PD-L1 immunohistochemistry (IHC) 22C3 companion diagnostic assay, which gives a tumor proportion score (TPS), has been validated on tumor tissue. We developed an optimized laboratory-developed test (LDT) that uses the 22C3 antibody (Ab) concentrate on a widely available IHC autostainer for biopsy and cytology specimens...
September 25, 2018: Journal of Visualized Experiments: JoVE
Xiaofeng Li, Qiang Fu, Yanjia Zhu, Jian Wang, Jianjing Liu, Xiaozhou Yu, Wengui Xu
The aim of this study is to investigate the role of CD147 in glucose metabolic regulation and its association with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment sensitivity prediction using 18 F-fluorodeoxyglucose (18 F-FDG) PET/CT imaging in non-small cell lung cancer (NSCLC). In this study, four human NSCLC cell lines with different EGFR-TKI responses were used to detect p-EGFR/EGFR and CD147 expression via western blotting and flow cytometric analyses. Radioactive uptake of 18 F-FDG by established stable NSCLC cell lines (HCC827, H1975) with different levels of CD147 expression and the corresponding xenografts was assessed through γ-radioimmunoassays in vitro and micro-PET/CT imaging in vivo to study the role of CD147 in glucose metabolic reprogramming...
October 15, 2018: Molecular Carcinogenesis
Lei Diao, Bernd Meibohm
Purpose of review: Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immunotherapy. This article provides a brief review of the application and key impact of pharmacometrics and quantitative clinical pharmacology approaches in the development of these novel biologics. Recent findings: The clinical development and selection of optimal dosing regimens for monoclonal antibodies used in immune-oncology has been facilitated by an extensive application of pharmacometric approaches to characterize the exposure-response relationship for major efficacy and safety endpoints...
August 2018: Current Pharmacology Reports
Federica Costa, Rituparna Das, Jithendra Kini Bailur, Kavita Dhodapkar, Madhav V Dhodapkar
Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as "immune checkpoints") including PD-1/PD-L1 has led to impressive tumor regressions in several cancers...
2018: Frontiers in Immunology
Mehmet Akce, Mohammad Y Zaidi, Edmund K Waller, Bassel F El-Rayes, Gregory B Lesinski
Pancreatic cancer has a dismal prognosis and effective treatment options are limited. It is projected to be the second most common cause of cancer related mortality in the United States by 2030 and there is urgent unmet need for novel systemic treatment options. Immunotherapy with antibodies targeting PD-1, PD-L1, CTLA-4 has not shown clinical activity in unselected pancreatic cancer, emphasizing the need for combination immunotherapy approaches or other therapeutic strategies. As such, chimeric antigen receptor (CAR) T cell therapy represents an emerging therapeutic option for pancreatic cancer...
2018: Frontiers in Immunology
Jean-David Fumet, Corentin Richard, Fanny Ledys, Quentin Klopfenstein, Philippe Joubert, Bertrand Routy, Caroline Truntzer, Andréanne Gagné, Marc-André Hamel, Camila Figueiredo Guimaraes, Bruno Coudert, Laurent Arnould, Laure Favier, Aurélie Lagrange, Sylvain Ladoire, Pierre Saintigny, Sandra Ortiz-Cuaran, Maurice Perol, Pascal Foucher, Paul Hofman, Marius Ilie, Sandy Chevrier, Romain Boidot, Valentin Derangere, François Ghiringhelli
BACKGROUND: No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC). METHODS: We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types...
October 15, 2018: British Journal of Cancer
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