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Cancer and immune checkpoint

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https://www.readbyqxmd.com/read/28096506/targeting-tnfr2-an-immune-checkpoint-stimulator-and-oncoprotein-is-a-promising-treatment-for-cancer
#1
REVIEW
Xin Chen, Joost J Oppenheim
Tumor necrosis factor receptor 2 (TNFR2) is expressed both by some cancer cells and by tumor-infiltrating immunosuppressive CD4(+)FoxP3(+) regulatory T cells (Tregs). TNFR2 stimulates the activation and proliferation of Tregs, a major checkpoint of antitumor immune responses, and promotes cancer cell survival and tumor growth. In this issue of Science Signaling, Torrey et al found that dominant antagonistic antibodies against human TNFR2 may be a potential therapy for ovarian cancer patients by simultaneously suppressing Treg activity and inducing the death of the cancer cells...
January 17, 2017: Science Signaling
https://www.readbyqxmd.com/read/28096505/the-neuropilin-2-isoform-nrp2b-uniquely-supports-tgf%C3%AE-mediated-progression-in-lung-cancer
#2
Robert M Gemmill, Patrick Nasarre, Joyce Nair-Menon, Federico Cappuzzo, Lorenza Landi, Armida D'Incecco, Hidetaka Uramoto, Takeshi Yoshida, Eric B Haura, Kent Armeson, Harry A Drabkin
Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non-small cell lung cancer (NSCLC) cell lines, transforming growth factor-β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models...
January 17, 2017: Science Signaling
https://www.readbyqxmd.com/read/28093620/inflammatory-bowel-disease-and-cancer-response-due-to-anti-ctla-4-is-it-in-the-flora
#3
REVIEW
Franck Carbonnel, Emilie Soularue, Clélia Coutzac, Nathalie Chaput, Christine Mateus, Patricia Lepage, Caroline Robert
Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab...
January 16, 2017: Seminars in Immunopathology
https://www.readbyqxmd.com/read/28090751/a-safety-checkpoint-to-eliminate-cancer-risk-of-the-immune-evasive-cells-derived-from-human-embryonic-stem-cells
#4
Jingjin He, Zhili Rong, Xuemei Fu, Yang Xu
Human embryonic stem cells (hESCs) hold great promise in the regenerative therapy of many currently untreatable human diseases. One of the key bottlenecks is the immune rejection of hESC-derived allografts by the recipient. To overcome this challenge, we have established new approaches to induce immune protection of hESC-derived allografts through the co-expression of immune suppressive molecules CTLA4-Ig and PD-L1. However, this in turn raises a safety concern of cancer risk because these hESC-derived cells can evade immune surveillance...
January 16, 2017: Stem Cells
https://www.readbyqxmd.com/read/28088513/an-immunogram-for-the-cancer-immunity-cycle-towards-personalized-immunotherapy-of-lung-cancer
#5
Takahiro Karasaki, Kazuhiro Nagayama, Hideki Kuwano, Jun-Ichi Nitadori, Masaaki Sato, Masaki Anraku, Akihiro Hosoi, Hirokazu Matsushita, Yasuyuki Morishita, Kosuke Kashiwabara, Masaki Takazawa, Osamu Ohara, Kazuhiro Kakimi, Jun Nakajima
INTRODUCTION: The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of anti-tumor immunity as a dynamic spacio-temporal process is required for each individual patient. To this end, we developed an immunogram for the cancer-immunity cycle using next-generation sequencing. METHODS: Whole-exome sequencing and RNA-Seq was performed in 20 non-small cell lung cancer patients (12 adenocarcinoma, 7 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma)...
January 11, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28088061/galectins-emerging-regulatory-checkpoints-linking-tumor-immunity-and-angiogenesis
#6
REVIEW
Santiago P Méndez-Huergo, Ada G Blidner, Gabriel A Rabinovich
Immune checkpoints, a plethora of inhibitory pathways aimed at maintaining immune cell homeostasis, may be co-opted by cancer cells to evade immune destruction. Therapies targeting immune checkpoints have reached a momentum yielding significant clinical benefits in patients with various malignancies by unleashing anti-tumor immunity. Galectins, a family of glycan-binding proteins, have emerged as novel regulatory checkpoints that promote immune evasive programs by inducing T-cell exhaustion, limiting T-cell survival, favoring expansion of regulatory T cells, de-activating natural killer cells and polarizing myeloid cells toward an immunosuppressive phenotype...
January 11, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28086852/pd-l1-expression-in-papillary-renal-cell-carcinoma
#7
Takanobu Motoshima, Yoshihiro Komohara, Chaoya Ma, Arni Kusuma Dewi, Hirotsugu Noguchi, Sohsuke Yamada, Toshiyuki Nakayama, Shohei Kitada, Yoshiaki Kawano, Wataru Takahashi, Masaaki Sugimoto, Motohiro Takeya, Naohiro Fujimoto, Yoshinao Oda, Masatoshi Eto
BACKGROUND: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2). METHODS: In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC). RESULT: We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen...
January 13, 2017: BMC Urology
https://www.readbyqxmd.com/read/28077173/is-cd47-an-innate-immune-checkpoint-for-tumor-evasion
#8
REVIEW
Xiaojuan Liu, Hyunwoo Kwon, Zihai Li, Yang-Xin Fu
Cluster of differentiation 47 (CD47) (also known as integrin-associated protein) is a ubiquitously expressed glycoprotein of the immunoglobulin superfamily that plays a critical role in self-recognition. Various solid and hematologic cancers exploit CD47 expression in order to evade immunological eradication, and its overexpression is clinically correlated with poor prognoses. One essential mechanism behind CD47-mediated immune evasion is that it can interact with signal regulatory protein-alpha (SIRPα) expressed on myeloid cells, causing phosphorylation of the SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and recruitment of Src homology 2 domain-containing tyrosine phosphatases to ultimately result in delivering an anti-phagocytic-"don't eat me"-signal...
January 11, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28076863/adverse-renal-effects-of-immune-checkpoint-inhibitors-a-narrative-review
#9
Rimda Wanchoo, Sabine Karam, Nupur N Uppal, Valerie S Barta, Gilbert Deray, Craig Devoe, Vincent Launay-Vacher, Kenar D Jhaveri
BACKGROUND: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patient's own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. SUMMARY: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity...
January 12, 2017: American Journal of Nephrology
https://www.readbyqxmd.com/read/28073132/hypothyroidism-in-cancer-patients-on-immune-checkpoint-inhibitors-with-anti-pd1-agents-insights-on-underlying-mechanisms
#10
M Alhusseini, J Samantray
Background: Immune therapy using monoclonal antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 receptor (PD-1) for various cancers have been reported to cause thyroid dysfunction. Little is known, however, about the underlying pathogenic mechanisms and the course of hypothyroidism that subsequently develops. In this report, we use the change in thyroglobulin and thyroid antibody levels in patients on immune therapy who develop hypothyroidism to better understand its pathogenesis as well as examine the status of hypothyroidism in the long term...
January 10, 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28070553/predicted-neoantigen-load-in-non-hypermutated-endometrial-cancers-correlation-with-outcome-and-tumor-specific-genomic-alterations
#11
Sachet A Shukla, Brooke E Howitt, Catherine J Wu, Panagiotis A Konstantinopoulos
Elevated neoantigen load has been previously correlated with improved outcome and response to immune checkpoint blockade in various tumor types. In endometrial cancer, previous studies of neoantigen load prediction have shown that the hypermutated MSI and POLE-mutated tumors harbor significantly higher predicted neoantigen load compared to the hypomutated CN-low/endometrioid and CN-high/serous-like tumors. Here, we report that predicted neoantigen load may be a prognostic factor in hypomutated endometrial cancers, both in CN-low/endometrioid and CN-high/serous-like tumors...
February 2017: Gynecologic Oncology Reports
https://www.readbyqxmd.com/read/28069723/a-novel-murine-gitr-ligand-fusion-protein-induces-antitumor-activity-as-a-monotherapy-which-is-further-enhanced-in-combination-with-an-ox40-agonist
#12
Rebecca Leyland, Amanda Watkins, Kathy Mulgrew, Nicholas Holoweckyj, Lisa Bamber, Natalie J Tigue, Emily Offer, John Andrews, Li Yan, Stefanie Mullins, Michael D Oberst, Jane Coates Ulrichsen, David A Leinster, Kelly A McGlinchey, Lesley Young, Michelle Morrow, Scott A Hammond, Philip R Mallinder, Athula Herath, Ching Ching Leow, Robert W Wilkinson, Ross Stewart
PURPOSE: To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy. EXPERIMENTAL DESIGN: The EC50 value of the mGITRL-FP was compared to an anti-GITR antibody in an in vitro agonistic cell based reporter assay. We assessed the impact of dose, schedule and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared to an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28064556/pd-1-checkpoint-blockade-alone-or-combined-pd-1-and-ctla-4-blockade-as-immunotherapy-for-lung-cancer
#13
Tawee Tanvetyanon, Jhanelle E Gray, Scott J Antonia
Signaling through T-cell surface, an immune checkpoint protein such as PD-1 or CTLA-4 helps dampen or terminate unwanted immune responses. Blocking a single immune checkpoint or multiple checkpoints simultaneously can generate anti-tumor activity against a variety of cancers including lung cancer. Area covered: This review highlights the results of recent clinical studies of single or combination checkpoint inhibitor immunotherapy in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The authors discuss pembrolizumab and pembrolizumab plus ipilimumab, durvalumab and durvalumab plus tremelimumab, nivolumab and nivolumab plus ipilimumab for NSCLC as well as nivolumab and nivolumab plus ipilimumab for SCLC...
January 9, 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28064139/neurological-adverse-events-associated-with-immune-checkpoint-inhibitors-review-of-the-literature
#14
REVIEW
S Cuzzubbo, F Javeri, M Tissier, A Roumi, C Barlog, J Doridam, C Lebbe, C Belin, R Ursu, A F Carpentier
Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3...
January 5, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28063623/immune-checkpoint-inhibitors-in-lung-cancer-an-unheralded-opportunity
#15
R Marshall, A Popple, T Kordbacheh, J Honeychurch, C Faivre-Finn, T Illidge
Lung cancer remains the leading cause of cancer-related death worldwide, with non-small cell lung cancer accounting for 85% of the disease. Over 70% of patients present with locally advanced, non-resectable or metastatic disease and despite improvements in chemoradiotherapy regimens and the development of molecularly targeted agents, 5 year survival rates remain poor, with acquired resistance to novel targeted therapies becoming a growing concern. Currently there remains an unmet need in effectively treating and inducing durable responses in advanced disease...
January 4, 2017: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/28061473/immunotherapy-incorporation-in-the-evolving-paradigm-of-renal-cancer-management-and-future-prospects
#16
Kenneth G Liu, Sorab Gupta, Sanjay Goel
Significant progress has been made in the management of renal cell carcinoma (RCC) during the last few decades. In early stage, localized disease, surgical resection remains the modality of choice, with no therapeutic interventions as options for post-operative therapy other than simple observation and clinical surveillance. However, treatment options in the advanced or metastatic setting are increasing at a dizzying pace, initially with cytokine therapy, then with the increased availability of targeted therapy including novel small-molecule inhibitors of receptor tyrosine kinases and monoclonal antibodies targeting novel proteins, establishing them as the current standard of care...
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28059852/immune-checkpoint-inhibitors-in-first-line-therapy-of-advanced-non-small-cell-lung-cancer
#17
Jordi Remon, Benjamin Besse
PURPOSE OF REVIEW: Evading immune destruction is a hallmark of cancer. The first therapeutic wave in immunotherapies comprised a series of monoclonal antibodies directed against the immune checkpoint molecules cytotoxic T-lymphocyte-associated protein 4, programmed death 1 (PD-1), and programmed death ligand-1 (PD-L1) revolutionizing the therapeutic landscape of advanced non-small cell lung cancer. They were validated initially as second-line treatment, becoming the new standard of care...
January 3, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28057932/dynamic-versus-static-biomarkers-in-cancer-immune-checkpoint-blockade-unravelling-complexity
#18
W Joost Lesterhuis, Anthony Bosco, Michael J Millward, Michael Small, Anna K Nowak, Richard A Lake
Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified; however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance...
January 6, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28057177/les-inhibiteurs-des-points-de-contr%C3%A3-le-immunitaire-dans-le-cancer-bronchique-non-%C3%A3-petites-cellules-de-stade-avanc%C3%A3
#19
Elizabeth Fabre, Nicola Pécuchet, Jacques Cadranel
IMMUNE CHECKPOINT INHIBITORS IN ADVANCED NON-SMALL CELL LUNG CANCER: T-cell-directed strategies represent currently a major advance in the treatment of advanced non-small-cell lung cancer, regarding their efficacy and tolerance. Nivolumab and pembrolizumab, two monoclonal antibodies targeting programmed cell death protein 1 (PD-1) have shown their efficacy in phase III studies. Several other drugs are developed and the benefit of association is being evaluated. In this article, we propose to summarize the clinical development of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer...
November 2016: Bulletin du Cancer
https://www.readbyqxmd.com/read/28055269/targeting-pd-1-pathway-a-new-hope-for-gastrointestinal-cancers
#20
Burak Bilgin, Mehmet An Sendur, Muhammed Bülent Akıncı, Didem Şener Dede, Bülent Yalçın
BACKGROUND: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most of the Gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aimed to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in the era of published or reported recent studies...
January 5, 2017: Current Medical Research and Opinion
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