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https://www.readbyqxmd.com/read/28328302/pembrolizumab-for-platinum-and-cetuximab-refractory-head-and-neck-cancer-results-from-a-single-arm-phase-ii-study
#1
Joshua Bauml, Tanguy Y Seiwert, David G Pfister, Francis Worden, Stephen V Liu, Jill Gilbert, Nabil F Saba, Jared Weiss, Lori Wirth, Ammar Sukari, Hyunseok Kang, Michael K Gibson, Erminia Massarelli, Steven Powell, Amy Meister, Xinxin Shu, Jonathan D Cheng, Robert Haddad
Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks...
March 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28327740/molecular-dynamics-simulations-elucidate-conformational-selection-and-induced-fit-mechanisms-in-the-binding-of-pd-1-and-pd-l1
#2
Wenping Liu, Bing Huang, Yashu Kuang, Guangjian Liu
Blockage of the interactions between immunologic checkpoint protein PD-1 and its ligand PD-L1 showed efficacy for cancer treatment. X-ray structures have captured static conformational snapshots of PD-1 and revealed that the CC' loop adopts an open conformation in the apo-protein but turns into a closed form and interacts with PD-L1 in the complex. This structural heterogeneity brings difficulties for structure-based drug discovery targeting PD-1. To gain insights into the role of the CC' loop in molecular recognition, we have undertaken a comparative study between the open and closed conformations in apo-PD-1 and the PD-1/PD-L1 complex using molecular dynamics simulations...
March 22, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28326832/nintedanib-plus-docetaxel-as-second-line-therapy-in-patients-with-non-small-cell-lung-cancer-of-adenocarcinoma-histology-a-network-meta-analysis-vs-new-therapeutic-options
#3
Sanjay Popat, Anders Mellemgaard, Martin Reck, Claudia Hastedt, Ingolf Griebsch
PATIENTS & METHODS: We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS: Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel, and versus nivolumab. Comparing nintedanib + docetaxel with nivolumab, hazards ratio (HR) of overall survival and progression-free survival (PFS) pointed in opposite directions (overall survival: HR: 1...
February 27, 2017: Future Oncology
https://www.readbyqxmd.com/read/28325255/mucosal-melanoma-of-the-head-and-neck
#4
REVIEW
Paolo Antonio Ascierto, Remo Accorona, Gerardo Botti, Davide Farina, Piero Fossati, Gemma Gatta, Helen Gogas, Davide Lombardi, Roberto Maroldi, Piero Nicolai, Marco Ravanelli, Vito Vanella
Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery...
April 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/28324831/primary-and-acquired-resistance-to-pd-1-pd-l1-blockade-in-cancer-treatment
#5
REVIEW
Qiaohong Wang, Xia Wu
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous...
March 18, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28324060/expression-of-pd-1-and-pd-l1-in-anaplastic-thyroid-cancer-patients-treated-with-multimodal-therapy-results-from-a-retrospective-study
#6
Ashish V Chintakuntlawar, Kandelaria M Rumilla, Carin Y Smith, Sarah M Jenkins, Robert L Foote, Jan L Kasperbauer, John C Morris, Mabel Ryder, Samer Alsidawi, Crystal Hilger, Keith C Bible
Context: Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of PD-1 and PD-L1 as prognostic and/or predictive marker in ATC is unknown. Objective: Multimodal therapy offers the best chance at tumor control. Objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC. Design: Retrospective study of a uniformly treated cohort. Setting: Single institution retrospective cohort study...
March 7, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28321814/immunotherapy-in-nsclc-a-promising-and-revolutionary-weapon
#7
Christian Rolfo, Christian Caglevic, Mariacarmela Santarpia, Antonio Araujo, Elisa Giovannetti, Carolina Diaz Gallardo, Patrick Pauwels, Mauricio Mahave
Lung cancer is the leader malignancy worldwide accounting 1.5 millions of deaths every year. In the United States the 5 year-overall survival is less than 20% for all the newly diagnosed patients. Cisplatin-based cytotoxic chemotherapy for unresectable or metastatic NSCLC patients in the first line of treatment, and docetaxel in the second line, have achieved positive results but with limited benefit in overall survival. Targeted therapies for EGFR and ALK mutant patients have showed better results when compared with chemotherapy, nevertheless most of patients will fail and need to be treated with chemotherapy if they still have a good performance status...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28321813/harnessing-the-immune-system-against-leukemia-monoclonal-antibodies-and-checkpoint-strategies-for-aml
#8
Lucia Masarova, Hagop Kantarjian, Guillermo Garcia-Mannero, Farhad Ravandi, Padmanee Sharma, Naval Daver
Acute myeloid leukemia (AML) is the most common leukemia among adults and is associated with a poor prognosis, especially in patients with adverse prognostic factors, older age, or relapsed disease. The last decade has seen a surge in successful immune-based therapies in various solid tumors; however, the role of immune therapies in AML remains poorly defined. This chapter describes the rationale, clinical data, and toxicity profiles of immune-based therapeutic modalities in AML including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, chimeric antigen receptor (CAR)-T cells, and checkpoint blockade via blockade of PD1/PDL1 or CTLA4...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28321130/effective-combinatorial-immunotherapy-for-castration-resistant-prostate-cancer
#9
Xin Lu, James W Horner, Erin Paul, Xiaoying Shang, Patricia Troncoso, Pingna Deng, Shan Jiang, Qing Chang, Denise J Spring, Padmanee Sharma, John A Zebala, Dean Y Maeda, Y Alan Wang, Ronald A DePinho
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance...
March 20, 2017: Nature
https://www.readbyqxmd.com/read/28319808/identifying-regulatory-posttranslational-modifications-of-pd-l1-a-focus-on-monoubiquitinaton
#10
Henrick Horita, Andy Law, Soonjin Hong, Kim Middleton
A set of high-affinity, high-specificity posttranslational modification (PTM) enrichment tools was developed to generate an unbiased snapshot of four key PTM profiles (tyrosine phosphorylation, acetylation, ubiquitination, and SUMOylation 2/3) for the clinically important protein programmed cell death ligand 1 (PD-L1). The results showed that epidermal growth factor (EGF) treatment induced tyrosine phosphorylation, acetylation, and ubiquitination of PD-L1. Further characterization of EGF-induced PD-L1 ubiquitination revealed a significant increase in mono- and multiubiquitination of PD-L1 that occurred on glycosylated PD-L1...
March 16, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28318951/a-comprehensive-analysis-of-programmed-cell-death-ligand-1-expression-with-the-clone-sp142-antibody-in-non-small-cell-lung-cancer%C3%A2-patients
#11
Kazuki Takada, Gouji Toyokawa, Tatsuro Okamoto, Mototsugu Shimokawa, Yuka Kozuma, Taichi Matsubara, Naoki Haratake, Takaki Akamine, Shinkichi Takamori, Masakazu Katsura, Fumihiro Shoji, Yoshinao Oda, Yoshihiko Maehara
BACKGROUND: Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti-PD-1 therapy currently the standard treatment for non-small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC...
March 2, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28317872/preclinical-evaluation-of-the-efficacy-pharmacokinetics-and-immunogenicity-of-js-001-a-programmed-cell-death-protein-1-pd-1-monoclonal-antibody
#12
Jie Fu, Fang Wang, Li-Hou Dong, Jing Zhang, Cheng-Lian Deng, Xue-Li Wang, Xin-Yao Xie, Jing Zhang, Ruo-Xian Deng, Li-Bo Zhang, Hai Wu, Hui Feng, Bo Chen, Hai-Feng Song
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28315964/biological-predictors-of-radiosensitivity-in-head-and-neck-squamous-cell-carcinoma
#13
Mathias Fiedler, Florian Weber, Matthias G Hautmann, Frank Haubner, Torsten E Reichert, Christoph Klingelhöffer, Stephan Schreml, Johannes K Meier, Arndt Hartmann, Tobias Ettl
OBJECTIVES: The aim of this study is to investigate the influence of prognostic biomarkers on radiosensitivity and survival of advanced head and neck squamous cell carcinomas treated by primary (chemo)radiation. MATERIAL AND METHODS: The clinicopathological data and immunohistochemical staining of p16, c-Met, survivin, PD-1, and PD-L1 of 82 primarily (chemo)irradiated patients with head and neck squamous cell carcinoma were analyzed. Associations with local and locoregional radiation response, overall survival (OS), disease-free (DFS), and disease-specific survival (DSS) were assessed...
March 18, 2017: Clinical Oral Investigations
https://www.readbyqxmd.com/read/28314962/pd-l1-expression-in-pancreatic-ductal-adenocarcinoma-is-a-poor-prognostic-factor-in-patients-with-high-cd8-tumor-infiltrating-lymphocytes-highly-sensitive-detection-using-phosphor-integrated-dot-staining
#14
So Yamaki, Hiroaki Yanagimoto, Koji Tsuta, Hironori Ryota, Masanori Kon
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. For the development of more effective immunotherapies, it is first necessary to elucidate the immunological escape mechanisms. In this study, we applied our recently developed highly sensitive immunostaining method employing fluorescent phosphor-integrated dot (PID) nanoparticles to evaluate the prevalence of programmed death ligand 1 (PD-L1) in patients with PDAC. METHODS: This study included 42 patients with PDAC who underwent pancreatectomy...
March 18, 2017: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28314758/immune-checkpoint-dysfunction-in-medium-and-large-vessel-vasculitis
#15
Ryu Watanabe, Hui Zhang, Gerald Berry, Jorg J Goronzy, Cornelia M Weyand
Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T-cells, macrophages and dendritic cells build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response-to-injury. Pathologic consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T-cells, but recent data suggest a more generalized defect in the threshold setting of such T-cells, rendering them hyperreactive...
March 17, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28314315/pd-l1-expression-is-a-prognostic-factor-in-patients-with-thoracic-esophageal-cancer-treated-without-adjuvant-chemotherapy
#16
Akiyuki Wakita, Satoru Motoyama, Hiroshi Nanjo, Yusuke Sato, Kei Yoshino, Tomohiko Sasaki, Yuta Kawakita, Jiajia Liu, Kazuhiro Imai, Hajime Saito, Yoshihiro Minamiya
BACKGROUND/AIM: Programmed death-1 ligand 1 (PD-L1) induces apoptosis of tumor-reactive T-cells, that enables tumors to evade immune defense and thus furthers their growth. Our aim was to determine whether PD-L1 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma. PATIENTS AND METHODS: The PD-L1 expression status of 177 patients treated with esophagectomy without preoperative therapy was evaluated immunohistochemically using tissue microarray...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28314313/pd-l1-expression-confers-better-prognosis-in-locally-advanced-oral-squamous-cell-carcinoma
#17
Yasunao Kogashiwa, Masanori Yasuda, Hiroyuki Sakurai, Mitsuhiko Nakahira, Yoshie Sano, Kenji Gonda, Tetsuya Ikeda, Hitoshi Inoue, Kiyomi Kuba, Susumu Oba, Junichi Ishikawa, Yuichiro Enoki, Satoko Matsumura, Kazuhiko Minami, Yasuhiro Ebihara, Masashi Sugasawa
BACKGROUND/AIM: Clinical trials with therapies targeting immune checkpoint molecules have shown promising results in several tumor types. However, the predictive and prognostic values of these immunological factors for locally advanced oral squamous cell carcinomas (LAOSCC) remain unclear. Our purpose was to evaluate the expression and prognostic value of programmed cell death-ligand1 (PD-L1) and PD-L2 and to correlate their expression with the degree of infiltration by CD8(+) cells in LAOSCC...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28314298/multi-omics-profiling-of-patients-with-melanoma-treated-with-nivolumab-in-project-hope
#18
Shusuke Yoshikawa, Yoshio Kiyohara, Masaki Otsuka, Ryota Kondou, Chizu Nonomura, Haruo Miyata, Akira Iizuka, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Masatoshi Kusuhara, Takashi Sugino, Tohru Mochizuki, Ken Yamaguchi, Yasuto Akiyama
BACKGROUND: Project HOPE (High-tech Omics-based Patient Evaluation) has been in progress since 2014 and uses whole-exome sequencing (WES) and gene expression profiling (GEP). Among a total of 1,685 patients with cancer, 13 with melanoma were registered and characterized using multi-omics analyses to investigate specific biomarkers in responders to programmed cell death-1 (PD-1) blockade. MATERIALS AND METHODS: The patients with melanoma comprised of six males and seven females, and their mean age was 68 years...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28306559/immunotherapy-a-new-treatment-paradigm-in-bladder-cancer
#19
Nicole N Davarpanah, Akira Yuno, Jane B Trepel, Andrea B Apolo
PURPOSE OF REVIEW: T-cell checkpoint blockade has become a dynamic immunotherapy for bladder cancer. In 2016, atezolizumab, an immune checkpoint inhibitor, became the first new drug approved in metastatic urothelial carcinoma (mUC) in over 30 years. In 2017, nivolumab was also approved for the same indication. This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy...
March 16, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28303311/-immunotherapy-of-cancer-with-checkpoint-inhibitors-not-only-in-malignant-melanoma
#20
A Neubauer
The newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research. The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic. Ipilimumab was the first monoclonal antibody developed against a target present on T cells after becoming activated, CTLA-4. In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide...
March 16, 2017: Der Internist
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