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pd1 AND lung cancer

Shan Feng, Xi Cheng, Lin Zhang, Xuemin Lu, Seema Chaudhary, Ruifang Teng, Christian Frederickson, Matthew M Champion, Ren Zhao, Liang Cheng, Yiyi Gong, Haiteng Deng, Xin Lu
Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs...
September 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Katerina Kachler, Corinna Holzinger, Denis I Trufa, Horia Sirbu, Susetta Finotto
Despite the opposite roles of Tbet and Foxp3 in the immune system as well as in tumour biology, recent studies have demonstrated the presence of of CD4+ T cells, expressing both, Tbet and Foxp3. Although Tbet+ Foxp3+ T cells are currently a subject of intense research, less is known about their biological function especially in cancer. Here we found a considerable accumulation of Tbet+ Foxp3+ CD4+ T cells, mediated by the immunosuppressive cytokine TGFβ in the lungs of tumour bearing mice. This is in line with previous studies, demonstrating the important role of TGFβ for the immunopathogenesis of cancer...
2018: Oncoimmunology
Kazuki Takada, Gouji Toyokawa, Tetsuzo Tagawa, Mototsugu Shimokawa, Kenichi Kohashi, Akira Haro, Atsushi Osoegawa, Yoshinao Oda, Yoshihiko Maehara
AIM: A combination of immune-checkpoint inhibitors that target the programmed cell death 1 (PD1)/programmed cell-death ligand 1 (PDL1) pathway and indoleamine 2,3-dioxygenase 1 (IDO1) is a promising treatment for non-small-cell lung cancer. Herein, we investigated clinical features of IDO1+ /PDL1+ primary lung adenocarcinoma. MATERIALS AND METHODS: IDO1 and PDL1 expression in 388 resected primary lung adenocarcinoma samples was evaluated using immunohistochemistry, and the radiological features of patients with IDO1+ /PDL1+ lung adenocarcinoma were analyzed...
September 2018: Anticancer Research
Alok Mishra, Mukesh Verma
Utilizing biology of PD-1: PD-L1 interaction related pathways for cancer immunotherapy is an emerging concept in cancer research. However, there is limited literature on epigenetic regulation of PD1 gene (PDCD1). Promising data from clinical trials of PD/PDl-1 immunotherapy in melanoma, renal cancers, colorectal and lung cancers has generated a lot of hope for successful treatment of patients. Immunotherapy in cancers has a significant role in strategizing NCI's Cancer Moonshot Program of US NIH and FDA policies...
2018: Methods in Molecular Biology
Rilan Bai, Naifei Chen, Jiuwei Cui
In recent years, epidermal growth factor receptor tyrosine kinase inhibitors have been recommended by many guidelines as first-line drugs for advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations and no resistance. However, with the prolongation of medication time, most appear acquired resistance. In recent years, breakthroughs in inhibitors of programmed death-1 (PD-1) and its ligand (PD1 ligand, PD-L1) have rapidly changed the therapeutic model of NSCLC. Recent studies have shown that the efficacy of immune checkpoint inhibitors in EGFR-mutant NSCLC patients is not satisfactory, which might be caused by low PD-L1 expression, inhibitory immune microenvironment and low tumor mutation load...
August 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Myra O Villareal, Yuki Sato, Kyoko Matsuyama, Hiroko Isoda
BACKGROUND: Melanoma is one of the most invasive and aggressive types of cancer with a very poor prognosis. Surgery remains the most efficient treatment prior melanoma invasion and metastasis formation. However, therapy becomes a challenge once the cancer cells colonized other tissues. At present, there are two main classes of therapies acting with a certain efficiency on metastatic melanoma: immune check point inhibitors (anti-PD1/PDL1) and targeted therapy such as Vemurafenib. Unfortunately, these therapies are not fully responsive, induce resistance and/or generate unwanted side effects...
August 29, 2018: BMC Cancer
David A Fabrizio, Thomas J George, Richard F Dunne, Garrett Frampton, James Sun, Kyle Gowen, Mark Kennedy, Joel Greenbowe, Alexa B Schrock, Aram F Hezel, Jeffrey S Ross, Phillip J Stephens, Siraj M Ali, Vincent A Miller, Marwan Fakih, Samuel J Klempner
Background: The clinical application of PD1/PD-L1 targeting checkpoint inhibitors in colorectal cancer (CRC) has largely focused on a subset of microsatellite instable (MSI-high) patients. However, the proposed genotype that sensitizes these patients to immunotherapy is not captured by MSI status alone. Estimation of tumor mutational burden (TMB) from comprehensive genomic profiling is validated against whole exome sequencing and linked to checkpoint response in metastatic melanoma, urothelial bladder cancer and non-small cell lung carcinoma...
August 2018: Journal of Gastrointestinal Oncology
Keith E Steele, Charles Brown
Multiplex immunohistochemistry allows the demonstration of multiple protein antigens in individual histological sections of formalin-fixed paraffin-embedded tumors or other types of tissue. Carefully designed and optimized immunohistochemistry (IHC) assays not only maximize the information available from limited tissues, but also enable a higher level interpretation of that information by demonstrating the histo-anatomical relationships among key cell types which express the included biomarkers. Programmable automated IHC instruments support the development and application of complicated multiplex IHC protocols, help save time and effort, and enhance immunostaining quality and reproducibility...
2018: Methods in Molecular Biology
Nataly Manjarrez-Orduño, Laurence C Menard, Selena Kansal, Paul Fischer, Bijal Kakrecha, Can Jiang, Mark Cunningham, Danielle Greenawalt, Vishal Patel, Minghui Yang, Ryan Golhar, Julie A Carman, Sergey Lezhnin, Hongyue Dai, Paul S Kayne, Suzanne J Suchard, Steven H Bernstein, Steven G Nadler
Agents targeting the PD1-PDL1 axis have transformed cancer therapy. Factors that influence clinical response to PD1-PDL1 inhibitors include tumor mutational burden, immune infiltration of the tumor, and local PDL1 expression. To identify peripheral correlates of the anti-tumor immune response in the absence of checkpoint blockade, we performed a retrospective study of circulating T cell subpopulations and matched tumor gene expression in melanoma and non-small cell lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose tumors exhibited increased inflammatory gene transcripts presented high CD4+ and CD8+ central memory T cell (CM) to effector T cell (Eff) ratios in blood...
2018: Frontiers in Immunology
Muhammad Khan, Jie Lin, Guixiang Liao, Yunhong Tian, Yingying Liang, Rong Li, Mengzhong Liu, Yawei Yuan
BACKGROUND: Recently, immune checkpoint inhibitors have shown survival advantage over chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). This meta-analysis was conducted to gather and analyze the available evidence (Evidence level I; Randomized Controlled Trials) comparing efficacy and safety of anti-programmed cell death-1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies and chemotherapy in the treatment of advanced NSCLC. METHODS: A search strategy was devised to identify the randomized controlled trials (RCTs) using electronic databases of PubMed, Cochrane Library, and Web of Science...
August 2018: Medicine (Baltimore)
Sebastian Kobold, Stanislav Pantelyushin, Felicitas Rataj, Johannes Vom Berg
T cells have been established as core effectors for cancer therapy; this has moved the focus of therapeutic endeavors to effectively enhance or restore T cell tumoricidal activity rather than directly target cancer cells. Both antibodies targeting the checkpoint inhibitory molecules programmed death receptor 1 (PD1), PD-ligand 1 (PD-L1) and cytotoxic lymphocyte activated antigen 4 (CTLA4), as well as bispecific antibodies targeting CD3 and CD19 are now part of the standard of care. In particular, antibodies to checkpoint molecules have gained broad approval in a number of solid tumor indications, such as melanoma or non-small cell lung cancer based on their unparalleled efficacy...
2018: Frontiers in Oncology
Weijing Cai, Dapeng Zhou, Weibo Wu, Wen Ling Tan, Jiaqian Wang, Caicun Zhou, Yanyan Lou
BACKGROUND: Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. RESULTS: In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules...
August 3, 2018: BMC Genomics
Olivier Bylicki, Nicolas Paleiron, Gaëlle Rousseau-Bussac, Christos Chouaïd
The advent of immune-checkpoint inhibitors during the past decade represents a major advancement in the treatment of non-small cell lung cancer (NSCLC) with personalized treatment. Platinum-based chemotherapy has reached its efficacy threshold, with its use remaining limited by its toxicity. For NSCLC, inhibitors of the PD1 protein and its ligand PDL1 show promising clinical activity and induce durable responses in patients with advanced disease. The US Food and Drug Administration has approved pembrolizumab for treatment-naïve metastatic NSCLC with ≥50% of tumor cells expressing PDL1 and for metastatic NSCLC with ≥1% PDL1 expression after progression following first-line platinum-based doublet chemotherapy...
2018: OncoTargets and Therapy
Jeremy M O'Connor, Kathi Seidl-Rathkopf, Aracelis Z Torres, Paul You, Kenneth R Carson, Joseph S Ross, Cary P Gross
Amid growing excitement for immune checkpoint inhibitors of programmed death protein 1 (anti-PD1 agents), little is known about whether race- or sex-based disparities exist in their use. In this observational study, we constructed a large and mostly community-based cohort of patients with advanced stage cancers, including melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma, to compare the odds of receiving systemic treatment with or without anti-PD1 agents by race and by sex. In multivariable models that adjusted for age, stage, and number of prior anticancer therapies, we found no significant race-based disparities in anti-PD1 treatment...
July 16, 2018: Oncologist
Marion Ferreira, Eric Pichon, Delphine Carmier, Emilie Bouquet, Cécile Pageot, Theodora Bejan-Angoulvant, Marion Campana, Emmanuelle Vermes, Sylvain Marchand-Adam
Immunotherapy medications that target programmed death 1 protein (PD-1) and programmed death-ligand 1 (PD-L1), such as nivolumab, pembrolizumab, and atezolizumab, are currently used in the first- or second-line treatment of non-small cell lung cancers, among other indications. However, these agents are associated with immune-related side effects, the most common of which are endocrinopathies, colitis, hepatitis, and interstitial pneumonitis. In contrast, coronary toxicities are rarely reported and remain poorly understood...
July 13, 2018: Targeted Oncology
Sebastian Kobold, Angela Krackhardt, Hans Schlösser, Dominik Wolf
Pioneering work has unraveled the role of the immune system in the development and control of cancer. This knowledge has set the basis for the successful implementation of immunotherapy into the standard of care for a large number of cancer types. Based on response rates and prolongation of overall survival, immunotherapeutic approaches have been approved in a growing number of tumor diseases. Activation or therapeutic utilization of T cells represent the basis of these concepts. Checkpoint inhibitory antibodies inhibiting CTLA-4, PD1 and PD-L1 receptors and ligands induce long-term clinical tumor control in a significant number of cancer patients including metastatic melanoma and non-small cell lung cancer...
July 2018: Deutsche Medizinische Wochenschrift
Jesus Miranda Poma, Lorena Ostios Garcia, Julia Villamayor Sanchez, Gabriele D'errico
Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs)...
July 5, 2018: Allergologia et Immunopathologia
Gianpiero Fasola, Elisa De Carlo, Francesco Grossi
The checkpoint inhibitors opened a new era in the treatment of advanced non-small-cell lung cancer (NSCLC) initially by replacing second-line standard chemotherapy with docetaxel and subsequently by replacing platinum-based chemotherapy in the first line, albeit in patients selected for a high expression of PD-L1. The decision algorithm has therefore been radically modified for patients who do not have activating mutations. However, we are only at the beginning of a new era from which we expect in the near future the use of immunotherapy in most patients as a first line treatment in substitution or in combination with chemotherapy...
June 2018: Recenti Progressi in Medicina
Jin-Hua Chen, Jia-Lian Yang, Che-Yi Chou, Jiun-Yi Wang, Chin-Chuan Hung
In this study, we conducted an indirect comparison analysis to compare the efficacy and safety of immune checkpoint inhibitors with those of antiangiogenic therapy-two effective treatment methods for advanced non-small-cell lung cancer (NSCLC). Eligible randomised control trials of immune checkpoint inhibitors, antiangiogenic therapy, and doublet platinum-based therapy published up to July 2017 were comprehensively analysed. Through the indirect comparison analysis of 37 trials involving 16810 patients, treatments were compared for overall survival (OS) and grade 3-5 adverse events...
June 26, 2018: Scientific Reports
Ana M Ramos-Levi, Jacobo Rogado, Jose Miguel Sanchez-Torres, Ramón Colomer, Mónica Marazuela
BACKGROUND: Nivolumab is an anti-cancer monoclonal antibody that inhibits PD1 and modulates T-cell response. It has been shown to significantly improve survival in several types of cancer, but clinical trials have also reported an increased risk of developing immune-related adverse events (IRAEs). Endocrine IRAEs may be particularly relevant. OBJECTIVE: To comprehensively evaluate the clinical presentation of endocrine IRAEs in patients with lung cancer treated with nivolumab...
June 14, 2018: Endocrinología, Diabetes y Nutrición
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