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https://www.readbyqxmd.com/read/28306559/immunotherapy-a-new-treatment-paradigm-in-bladder-cancer
#1
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
#2
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
https://www.readbyqxmd.com/read/28289860/the-pd-l1-pd-1-pathway-promotes-dysfunction-but-not-exhaustion-in-tumor-responding-t-cells-from-pleural-effusions-in-lung-cancer-patients
#3
Heriberto Prado-Garcia, Susana Romero-Garcia, Alejandra Puerto-Aquino, Uriel Rumbo-Nava
Malignant pleural effusions are frequent in patients with advanced stages of lung cancer and are commonly infiltrated by lymphocytes and tumor cells. CD8+ T cells from these effusions have reduced effector functions. The programmed death receptor 1(PD-1)/programmed death ligand 1 (PD-L1) pathway is involved in T-cell exhaustion, and it might be responsible for T-cell dysfunction in lung cancer patients. Here, we show that PD-L1 is expressed on tumor cell samples from malignant effusions, on lung cancer cell lines, and, interestingly, on MRC-5 lung fibroblasts...
March 13, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28287115/efficient-control-of-chronic-lcmv-infection-by-a-cd4-t-cell-epitope-based-heterologous-prime-boost-vaccination-in-a-murine-model
#4
Ran He, Xinxin Yang, Cheng Liu, Xiangyu Chen, Lin Wang, Minglu Xiao, Jianqiang Ye, Yuzhang Wu, Lilin Ye
CD4(+) T cells are essential for sustaining CD8(+) T cell responses during a chronic infection. The adoptive transfer of virus-specific CD4(+) T cells has been shown to efficiently rescue exhausted CD8(+) T cells. However, the question of whether endogenous virus-specific CD4(+) T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8(+) T cells remains unexplored. In this study, we developed a CD4(+) T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection...
March 13, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28285915/adamantyl-and-other-polycyclic-cage-based-conjugates-of-desferrioxamine-b-dfob-for-treating-iron-mediated-toxicity-in-cell-models-of-parkinson-s-disease
#5
Thomas J Telfer, Jeffrey R Liddell, Clare Duncan, Anthony R White, Rachel Codd
The death of dopaminergic neurons is a major pathological hallmark of Parkinson's disease (PD). Elevated iron within the substantia nigra of the PD brain is thought to catalyze this neuronal death through hydroxyl radical-derived oxidative damage. Removing this excess iron presents a potential therapeutic strategy for PD. Seventeen derivatives of the non-toxic iron chelator desferrioxamine B (DFOB) were prepared by the conjugation of adamantyl- (1-4, 8-12), deconstructed adamantyl units (5-7), norborna(e)ne- (13-16) or bicyclo[2...
March 2, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28285682/pretreatment-neutrophil-to-lymphocyte-ratio-as-a-marker-of-outcomes-in-nivolumab-treated-patients-with-advanced-non-small-cell-lung-cancer
#6
Stephen J Bagley, Shawn Kothari, Charu Aggarwal, Joshua M Bauml, Evan W Alley, Tracey L Evans, John A Kosteva, Christine A Ciunci, Peter E Gabriel, Jeffrey C Thompson, Susan Stonehouse-Lee, Victoria E Sherry, Elizabeth Gilbert, Beth Eaby-Sandy, Faith Mutale, Gloria DiLullo, Roger B Cohen, Anil Vachani, Corey J Langer
OBJECTIVES: Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)<5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab. METHODS: We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania...
April 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28284988/frequencies-of-pd-1-positive-t-cd3-cd4-t-cd3-cd8-and-b%C3%A2-cd19-lymphocytes-in-female-patients-with-graves-disease-and-healthy-controls-preliminary-study
#7
Aleksandra Pyzik, Ewelina Grywalska, Beata Matyjaszek-Matuszek, Agata Smoleń, Dawid Pyzik, Jacek Roliński
PD-1 maintains tolerance and inhibits autoimmune responses. Graves' disease (GD) is one of the most frequent autoimmune diseases of unclear etiology. The aim of this study was to evaluate the percentage and absolute counts of PD-1 positive T and B cells in newly diagnosed, untreated patients with hyperthyroidism due to GD. The study group included 30 patients and the control group comprised of 20 age- and sex-matched healthy individuals. Results showed significantly higher frequencies and absolute counts of PD-1 positive CD3+CD4+ T cells, CD3+CD8+ T cells and CD19+B cells in patients with GD in comparison to the healthy volunteers...
March 8, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28279032/-a-clinical-analysis-of-10-cases-with-cardiac-lymphoma
#8
Y H Li, C Y Shi, F Q Duan, Y Pang, H B Li, L Q Zhang, Z H Liu, L Ouyang, C Y Yue, M C Xie, Z J Jiang, Y Xiao
Objective: To analyze the morbidity, clinical characteristics, therapeutic outcomes and prognosis of cardiac lymphoma. Methods: Individual patient data were obtained from pathology defined 10 cases of cardiac lymphoma from Jan 2000 to Jun 2016. The patient's general information, clinical manifestation, pathological diagnosis, laboratory examination, cardiac involvement feature, cardiac complications, treatment, therapeutic effect and prognosis were analyzed. Results: Of 3 918 cases of lymphoma patients, 10 cases of cardiac involvement were identified, including primary cardiac lymphoma (PCL) in 1 case, secondary cardiac lymphoma (SCL) in 9 cases...
February 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28278348/a-prospective-multi-institutional-pathologist-based-assessment-of-4-immunohistochemistry-assays-for-pd-l1-expression-in-non-small-cell-lung-cancer
#9
David L Rimm, Gang Han, Janis M Taube, Eunhee S Yi, Julia A Bridge, Douglas B Flieder, Robert Homer, William W West, Hong Wu, Anja C Roden, Junya Fujimoto, Hui Yu, Robert Anders, Ashley Kowalewski, Christopher Rivard, Jamaal Rehman, Cory Batenchuk, Virginia Burns, Fred R Hirsch, Ignacio I Wistuba
Importance: Four assays registered with the US Food and Drug Administration (FDA) detect programmed cell death ligand 1 (PD-L1) to enrich for patient response to anti-programmed cell death 1 and anti-PD-L1 therapies. The tests use 4 separate PD-L1 antibodies on 2 separate staining platforms and have their own scoring systems, which raises questions about their similarity and the potential interchangeability of the tests. Objective: To compare the performance of 4 PD-L1 platforms, including 2 FDA-cleared assays, 1 test for investigational use only, and 1 laboratory-developed test...
March 9, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28276272/gut-brain-and-brain-gut-axis-in-parkinson-s-disease-models-effects-of-a-uridine-and-fish-oil-diet
#10
Paula Perez-Pardo, Hemraj B Dodiya, Laus M Broersen, Hidde Douna, Nick van Wijk, Sofia Lopes da Silva, Johan Garssen, Ali Keshavarzian, Aletta D Kraneveld
Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this 'dual-hit hypothesis' and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models...
March 9, 2017: Nutritional Neuroscience
https://www.readbyqxmd.com/read/28275115/safety-and-tolerability-of-pd-1-pd-l1-inhibitors-compared-with-chemotherapy-in-patients-with-advanced-cancer-a-meta-analysis
#11
Tomohiro F Nishijima, Shlomit S Shachar, Kirsten A Nyrop, Hyman B Muss
BACKGROUND: Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy. METHODS: PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016...
March 8, 2017: Oncologist
https://www.readbyqxmd.com/read/28274048/evaluation-of-cyclosporine-a-with-%C3%AE-tcp-in-the-treatment-of-human-infra-bony-defects-a-randomized-controlled-pilot-study
#12
Jyotsna Amalakara, Krishnajaneya Reddy, Haritha Avula, Ashank Mishra, Butchibabu Kalakonda, Ruchi Pandey
INTRODUCTION: Cyclosporine A (CsA), an immunosuppressant, is considered a life saver drug in organ transplant cases. It has also been tested in animal and human studies for periodontal applications as it selectively inhibits T lymphocyte proliferation, Interleukin-2 (IL-2) and other cytokine production, without any effect on T suppressor cells, thereby suppressing the cell mediated immunity and suppressing the inflammation. Inflammatory and immunological responses have been found to be decreased and bone formation is found to be increased in immunosuppressed animals...
January 2017: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28262555/membrane-proximal-epitope-facilitates-efficient-t-cell-synapse-formation-by-anti-fcrh5-cd3-and-is-a-requirement-for-myeloma-cell-killing
#13
Ji Li, Nicola J Stagg, Jennifer Johnston, Michael J Harris, Sam A Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R James, Teemu T Junttila
The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys...
February 20, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28257800/human-mesenchymal-stem-cell-educated-macrophages-are-a-distinct-high-il-6-producing-subset-that-confer-protection-in-graft-versus-host-disease-and-radiation-injury-models
#14
Myriam N Bouchlaka, Andrea B Moffitt, Jaehyup Kim, John A Kink, Debra D Bloom, Cassandra Love, Sandeep Dave, Peiman Hematti, Christian M Capitini
Mesenchymal stem cells (MSCs) have immunosuppressive and tissue repair properties, but clinical trials using MSCs to prevent or treat GVHD have shown mixed results. Macrophages (MØs) are important regulators of immunity and can promote tissue regeneration and remodeling. We have previously shown that MSCs can educate MØs toward a unique anti-inflammatory immunophenotype (MSC-educated macrophages or MEMs), however their implications for in vivo models of inflammation have not been studied yet. We now show that in comparison to MØs, MEMs have increased expression of the inhibitory molecules PD-L1, PD-L2, in addition to markers of alternatively activated macrophages: CD206 and CD163...
February 28, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#15
Simon J Hogg, Stephin J Vervoort, Sumit Deswal, Christopher J Ott, Jason Li, Leonie A Cluse, Paul A Beavis, Phillip K Darcy, Benjamin P Martin, Andrew Spencer, Anna K Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E Bradner, Johannes Zuber, Jake Shortt, Ricky W Johnstone
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28246107/comprehensive-meta-analysis-of-key-immune-related-adverse-events-from-ctla-4-and-pd-1-pd-l1-inhibitors-in-cancer-patients
#16
Guillermo De Velasco, Youjin Je, Dominick Bossé, Mark M Awad, Patrick A Ott, Raphael B Moreira, Fabio A B Schutz, Joaquim Bellmunt, Guru Sonpavde, F Stephen Hodi, Toni K Choueiri
Immune-related adverse events (irAEs) have been described with immune checkpoint inhibitors (ICIs), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016...
February 28, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28244186/cerebrospinal-fluid-levels-of-catecholamines-and-its-metabolites-in-parkinson-s-disease-effect-of-l-dopa-treatment-and-changes-in-levodopa-induced-dyskinesia
#17
A D Andersen, M Blaabjerg, M Binzer, A Kamal, H Thagesen, T W Kjaer, E Stenager, J B Gramsbergen
Levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to L-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily L-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID (PD-LID, n=8)) as compared to non-dyskinetic PD patients receiving L-DOPA (PD-L, n=6), or not receiving L-DOPA (PD-N, n=7) as well as non-PD controls (n=16)...
February 28, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28237836/inhibitory-receptors-induced-by-vsv-viroimmunotherapy-are-not-necessarily-targets-for-improving-treatment-efficacy
#18
Kevin G Shim, Shane Zaidi, Jill Thompson, Tim Kottke, Laura Evgin, Karishma R Rajani, Matthew Schuelke, Christopher B Driscoll, Amanda Huff, Jose S Pulido, Richard G Vile
Systemic viroimmunotherapy activates endogenous innate and adaptive immune responses against both viral and tumor antigens. We have shown that therapy with vesicular stomatitis virus (VSV) engineered to express a tumor-associated antigen activates antigen-specific adoptively transferred T cells (adoptive cell therapy, ACT) in vivo to generate effective therapy. The overall goal of this study was to phenotypically characterize the immune response to VSV+ACT therapy and use the information gained to rationally improve combination therapy...
February 22, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28228726/current-diagnosis-and-management-of-immune-related-adverse-events-iraes-induced-by-immune-checkpoint-inhibitor-therapy
#19
REVIEW
Vivek Kumar, Neha Chaudhary, Mohit Garg, Charalampos S Floudas, Parita Soni, Abhinav B Chandra
The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agents like tremelimumab and atezolimumab for use in patients with advanced stage mesothelioma and urothelial carcinoma respectively. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28223273/pd-l1-studies-across-tumor-types-its-differential-expression-and-predictive-value-in-patients-treated-with-immune-checkpoint-inhibitors
#20
Harriet M Kluger, Christopher R Zito, Gabriela Turcu, Marina Baine, Hongyi Zhang, Adebowale Adeniran, Mario Sznol, David L Rimm, Yuval Kluger, Lieping Chen, Justine V Cohen, Lucia B Jilaveanu
PURPOSE: With recent approval of inhibitors of PD-1 in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC), extensive efforts are underway to develop biomarkers predictive of response. PD-L1 expression has been most widely studied, and is more predictive in NSCLC than RCC or melanoma. We therefore studied differences in expression patterns across tumor types. EXPERIMENTAL DESIGN: We employed tissue microarrays with tumors from NSCLC, RCC or melanoma and a panel of cell lines to study differences between tumor types...
February 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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