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https://www.readbyqxmd.com/read/29164593/immune-correlates-of-clinical-outcome-in-melanoma
#1
REVIEW
Graham Pawelec
Melanoma has long been recognized as a potentially immunogenic tumour, but only recently has it become clear that the reason for this resides in its many UV-induced mutations and expression of multiple autoantigens which can be targeted by the immune system. The first successful applications of immune-based treatments included passive immunotherapy using high-dose IL-2 and/or adoptive transfer of NK-cells, as well as active immunotherapy using whole cell-derived or peptide vaccines. In the intervening decades, it has become clear that these approaches can lead to durable responses in stage III/IV melanoma, and even to functional cures - but only in a vanishingly small fraction of patients...
November 21, 2017: Immunology
https://www.readbyqxmd.com/read/29164492/advanced-melanoma-current-treatment-options-biomarkers-and-future-perspectives
#2
REVIEW
Elisa A Rozeman, Tim J A Dekker, John B A G Haanen, Christian U Blank
Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities...
November 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29163851/checkpoint-inhibitors-in-endometrial-cancer-preclinical-rationale-and-clinical-activity
#3
REVIEW
Gloria Mittica, Eleonora Ghisoni, Gaia Giannone, Massimo Aglietta, Sofia Genta, Giorgio Valabrega
Context: Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163543/interleukin-6-present-in-inflammatory-ascites-from-advanced-epithelial-ovarian-cancer-patients-promotes-tumor-necrosis-factor-receptor-2-expressing-regulatory-t-cells
#4
Nirmala Chandralega Kampan, Mutsa Tatenda Madondo, Orla M McNally, Andrew N Stephens, Michael A Quinn, Magdalena Plebanski
Background: Epithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29163490/immune-checkpoint-molecules-on-tumor-infiltrating-lymphocytes-and-their-association-with-tertiary-lymphoid-structures-in-human-breast-cancer
#5
Cinzia Solinas, Soizic Garaud, Pushpamali De Silva, Anaïs Boisson, Gert Van den Eynden, Alexandre de Wind, Paolo Risso, Joel Rodrigues Vitória, François Richard, Edoardo Migliori, Grégory Noël, Hugues Duvillier, Ligia Craciun, Isabelle Veys, Ahmad Awada, Vincent Detours, Denis Larsimont, Martine Piccart-Gebhart, Karen Willard-Gallo
There is an exponentially growing interest in targeting immune checkpoint molecules in breast cancer (BC), particularly in the triple-negative subtype where unmet treatment needs remain. This study was designed to analyze the expression, localization, and prognostic role of PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM3 in primary BC. Gene expression analysis using the METABRIC microarray dataset found that all six immune checkpoint molecules are highly expressed in basal-like and HER2-enriched compared to the other BC molecular subtypes...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29161463/the-il-21-mtor-axis-blocks-treg-differentiation-and-function-by-suppression-of-autophagy-in-patients-with-systemic-lupus-erythematosus
#6
Hiroshi Kato, Andras Perl
OBJECTIVES: The mechanistic target of rapamycin (mTOR) has become a therapeutic target in systemic lupus erythematosus (SLE). mTOR regulates normal T-cell lineage specification, including development of regulatory cells (Tregs). Therefore, we investigated whether mTOR is activated within Tregs and causes their depletion and dysfunction in patients with SLE. METHODS: Activities of mTOR complexes 1 (mTORC1) and 2 (mTORC2) were examined by phosphorylation of 4E-BP1, S6K, and Akt, respectively, in SLE patients relative to healthy control females age-matched for each experiment...
November 21, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29155997/immune-activation-and-benefit-from-avelumab-in-ebv-positive-gastric-cancer
#7
Anshuman Panda, Janice M Mehnert, Kim M Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Michael Kane, Levi Sokol, Mark N Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann W Silk, Joseph Aisner, Nancy Chan, Jyoti Malhotra, Melissa Frankel, Howard L Kaufman, Siraj Ali, Jeffrey S Ross, Eileen P White, Gyan Bhanot, Shridar Ganesan
Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS...
November 15, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29150430/interferon-%C3%A1%C2%B5-2-signaling-in-melanocytes-and-melanoma-cells-regulates-expression-of-ctla-4
#8
Xuan Mo, Hanghang Zhang, Sarah Preston, Kayla Martin, Bo Zhou, Nish Vadalia, Ana M Gamero, Jonathan Soboloff, Italo Tempera, M Raza Zaidi
CTLA-4 is a cell surface receptor on T cells that functions as an immune checkpoint molecule to enforce tolerance to cognate antigens. Anti-CTLA-4 immunotherapy is highly effective at reactivating T cell responses against melanoma, which is postulated to be due to targeting CTLA-4 on T cells. Here we report that CTLA-4 is also highly expressed by most human melanoma cell lines, as well as in normal human melanocytes. Interferon-gamma (IFNG) signaling activated the expression of the human CTLA-4 gene in a melanocyte and melanoma cell-specific manner...
November 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/29149705/toll-like-receptor-4-deficiency-increases-resistance-in-sepsis-induced-immune-dysfunction
#9
Chao Cao, Yanfen Chai, Songtao Shou, Jun Wang, Ying Huang, Tao Ma
Sepsis constitutes a serious life-threatening syndrome associated with complications of deregulated inflammatory response against endotoxin/lipopolysaccharide (LPS)-mediated severe infection. Toll-like receptor 4 (TLR4) plays a critical role in the activation of innate immunity through recognition of LPS. However, the impact of TLR4 signaling on the development of sepsis-induced immune dysfunction remains unclear. The aim of this study was to investigate the effect of TLR4 on regulatory T cells (Tregs) and its potential mechanism...
November 14, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29147453/ctla-4-genetic-variants-rs11571317-and-rs3087243-role-in-susceptibility-and-progression-of-breast-cancer
#10
Maruthi Goske, V R Vinish Ramachander, Prasanna Latha Komaravalli, P Fazul Rahman, Chandrasekhar Rao, Parveen Jahan
Background: Dysfunctional regulation at immune checkpoints may lead to escape of the tumor cells and gives a scope to set in the unresolved Breast cancer (BC). The major anti-tumor retort is cell-mediated response which involves T lymphocytes. CTLA-4 (Cytotoxic T lymphocyte associated protein-4) with immune suppressive function and tolerance is associated with various autoimmune diseases and cancers including BC. The present study deals with CTLA-4 gene selected polymorphisms (rs11571317 C/T and rs3087243G/A) to explore their relation with breast cancer susceptibility and progression in BC patients...
October 2017: World Journal of Oncology
https://www.readbyqxmd.com/read/29145543/association-of-ipilimumab-with-safety-and-antitumor-activity-in-women-with-metastatic-or-recurrent-human-papillomavirus-related-cervical-carcinoma
#11
Stephanie Lheureux, Marcus O Butler, Blaise Clarke, Mihaela C Cristea, Lainie P Martin, Katia Tonkin, Gini F Fleming, Anna V Tinker, Hal W Hirte, Daliah Tsoref, Helen Mackay, Neesha C Dhani, Prafull Ghatage, Johanne Weberpals, Stephen Welch, Nhu-An Pham, Vinicius Motta, Valentin Sotov, Lisa Wang, Katherine Karakasis, Smitha Udagani, Suzanne Kamel-Reid, Howard Z Streicher, Patricia Shaw, Amit M Oza
Importance: Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective: To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants: A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy...
November 16, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29145036/liver-immunotolerance-and-hepatocellular-carcinoma-patho-physiological-mechanisms-and-therapeutic-perspectives
#12
REVIEW
Gaël S Roth, Thomas Decaens
At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1...
November 13, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29143108/immune-checkpoint-inhibitor-colitis-the-flip-side-of-the-wonder-drugs
#13
Naziheh Assarzadegan, Elizabeth Montgomery, Robert A Anders
Immune checkpoint inhibitors block the co-inhibitory receptors on T cells to activate their cytotoxic immune function and are rapidly being explored for the treatment of various advanced-stage malignancies. These novel drugs have already significantly increased survival rates. The first available immune checkpoint inhibitors were cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors (such as ipilimumab), followed by programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors (such as pembrolizumab and nivolumab)...
November 15, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29142180/review-on-recent-topics-in-hypophysitis
#14
Hitoshi Sugihara
The number of cases of lymphocytic hypophysitis is small, although the condition is not rare. For optimal therapy, the correct diagnosis from imaging, immunological studies, and pathological findings from a pituitary biopsy is important. Recently, anti-Rabphilin antibody has been proposed to be a biomarker for lymphocytic infundibulo-neurohypophysitis. Immunological disorders such as anti-Pit-1 antibody syndrome are similar to the pathogenesis of lymphocytic hypophysitis. Moreover, recent immune checkpoint blockade such ipilimumab has been shown to induce anti-CTLA-4-related hypophysitis...
2017: Journal of Nippon Medical School, Nippon Ika Daigaku Zasshi
https://www.readbyqxmd.com/read/29141863/eight-color-multiplex-immunohistochemistry-for-simultaneous-detection-of-multiple-immune-checkpoint-molecules-within-the-tumor-microenvironment
#15
Mark A J Gorris, Altuna Halilovic, Katrin Rabold, Anne van Duffelen, Iresha N Wickramasinghe, Dagmar Verweij, Inge M N Wortel, Johannes C Textor, I Jolanda M de Vries, Carl G Figdor
Therapies targeting immune checkpoint molecules CTLA-4 and PD-1/PD-L1 have advanced the field of cancer immunotherapy. New mAbs targeting different immune checkpoint molecules, such as TIM3, CD27, and OX40, are being developed and tested in clinical trials. To make educated decisions and design new combination treatment strategies, it is vital to learn more about coexpression of both inhibitory and stimulatory immune checkpoints on individual cells within the tumor microenvironment. Recent advances in multiple immunolabeling and multispectral imaging have enabled simultaneous analysis of more than three markers within a single formalin-fixed paraffin-embedded tissue section, with accurate cell discrimination and spatial information...
November 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29140541/regulatory-t-cells-in-acute-dengue-viral-infection
#16
Eresha Jayaratne, Dulharie Wijeratne, Samitha Fernando, Achala Kamaladasa, Laksiri Gomes, Ananda Wijewickrama, Graham Stuart Ogg, Gathsaurie Neelika Malavige
Although regulatory T cells (Tregs) have been shown to be expanded in acute dengue, their role in pathogenesis and their relationship to clinical disease severity, and extent of viraemia have not been fully evaluated. The frequency of Tregs was assessed in 56 adult patients with acute dengue, by determining the proportion of FOXP3 expressing CD4(+) CD25(+) T cells (FOXP3+ cells). DENV viral loads were measured by quantitative real time PCR and DENV specific T cell responses were measured by ex vivo IFNγ ELISpot assays to overlapping peptide pools of DENV-NS3, NS1 and NS5...
November 15, 2017: Immunology
https://www.readbyqxmd.com/read/29140105/durvalumab-in-non-small-cell-lung-cancer-patients-current-developments
#17
Laura Mezquita, David Planchard
Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy...
November 15, 2017: Future Oncology
https://www.readbyqxmd.com/read/29139554/immune-checkpoint-inhibitors-new-strategies-to-checkmate-cancer
#18
REVIEW
Ruairi A M Wilson, T R Jeffry Evans, Alasdair R Fraser, Robert J B Nibbs
Immune checkpoint inhibitors (ICIs) targeting Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) or Programmed cell Death protein 1 (PD-1) receptors have demonstrated remarkable efficacy in subsets of patients with malignant disease. This emerging treatment modality holds great promise for future cancer treatment and has engaged pharmaceutical research interests in tumour immunology. While ICIs can induce rapid and durable responses in some patients, identifying predictive factors for effective clinical responses has proven challenging...
November 15, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/29138342/immunotherapy-of-hepatocellular-carcinoma-facts-and-hopes
#19
Mercedes Iñarrairaegui, Ignacio Melero, Bruno Sangro
Treatment of patients with hepatocellular carcinoma in the advanced stage remains a great challenge, with very few drugs approved. After decades of failures of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with hepatocellular carcinoma in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells, and mostly provide immunosuppressive signals...
November 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29137242/immune-profiling-of-nf1-associated-tumors-reveals-histologic-subtype-distinctions-and-heterogeneity-implications-for-immunotherapy
#20
Kellie B Haworth, Michael A Arnold, Christopher R Pierson, Kwangmin Choi, Nicholas D Yeager, Nancy Ratner, Ryan D Roberts, Jonathan L Finlay, Timothy P Cripe
Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles...
October 10, 2017: Oncotarget
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