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https://www.readbyqxmd.com/read/29150430/interferon-%C3%A1%C2%B5-2-signaling-in-melanocytes-and-melanoma-cells-regulates-expression-of-ctla-4
#1
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/29145543/association-of-ipilimumab-with-safety-and-antitumor-activity-in-women-with-metastatic-or-recurrent-human-papillomavirus-related-cervical-carcinoma
#2
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/29143108/immune-checkpoint-inhibitor-colitis-the-flip-side-of-the-wonder-drugs
#3
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
#4
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/29138342/immunotherapy-of-hepatocellular-carcinoma-facts-and-hopes
#5
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/29132144/a-neoantigen-fitness-model-predicts-tumour-response-to-checkpoint-blockade-immunotherapy
#6
Marta Łuksza, Nadeem Riaz, Vladimir Makarov, Vinod P Balachandran, Matthew D Hellmann, Alexander Solovyov, Naiyer A Rizvi, Taha Merghoub, Arnold J Levine, Timothy A Chan, Jedd D Wolchok, Benjamin D Greenbaum
Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: the likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells...
November 8, 2017: Nature
https://www.readbyqxmd.com/read/29129918/intratumoral-cd40-activation-and-checkpoint-blockade-induces-t-cell-mediated-eradication-of-melanoma-in-the-brain
#7
Manisha Singh, Christina Vianden, Mark J Cantwell, Zhimin Dai, Zhilan Xiao, Meenu Sharma, Hiep Khong, Ashvin R Jaiswal, Faisal Faak, Yared Hailemichael, L M E Janssen, Uddalak Bharadwaj, Michael A Curran, Adi Diab, Roland L Bassett, David J Tweardy, Patrick Hwu, Willem W Overwijk
CD40 agonists bind the CD40 molecule on antigen-presenting cells and activate them to prime tumor-specific CD8(+) T cell responses. Here, we study the antitumor activity and mechanism of action of a nonreplicating adenovirus encoding a chimeric, membrane-bound CD40 ligand (ISF35). Intratumoral administration of ISF35 in subcutaneous B16 melanomas generates tumor-specific, CD8(+) T cells that express PD-1 and suppress tumor growth. Combination therapy of ISF35 with systemic anti-PD-1 generates greater antitumor activity than each respective monotherapy...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29113324/unfolded-protein-response-signaling-impacts-macrophage-polarity-to-modulate-breast-cancer-cell-clearance-and-melanoma-immune-checkpoint-therapy-responsiveness
#8
David R Soto-Pantoja, Adam S Wilson, Kenysha Yj Clear, Brian Westwood, Pierre L Triozzi, Katherine L Cook
The unfolded protein response (UPR) is a stress pathway controlled by GRP78 to mediate IRE1, PERK, and ATF6 signaling. We show that targeting GRP78, IRE1, and PERK differentially regulates macrophage polarization. Specifically, PERK targeting enhanced macrophage proliferation and macrophage-mediated killing but not GRP78 or IRE1. Targeting UPR in cancer cells also differentially affected macrophage cytolytic capacity. Tumoral IRE1 or GRP78 inhibition enhanced macrophage-mediated cancer cell clearance. Conditioned media from GRP78-silenced cancer cells caused reciprocal regulation of CD80 and CD206, suggesting control of plasticity by secreted factors...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29108362/baseline-relative-eosinophil-count-as-a-predictive-biomarker-for-ipilimumab-treatment-in-advanced-melanoma
#9
Pier Francesco Ferrucci, Sara Gandini, Emilia Cocorocchio, Laura Pala, Federica Baldini, Massimo Mosconi, Gian Carlo Antonini Cappellini, Elena Albertazzi, Chiara Martinoli
As diverse therapeutic options are now available for advanced melanoma patients, predictive markers that may assist treatment decision are needed. A model based on baseline serum lactate dehydrogenase (LDH), peripheral blood relative lymphocyte counts (RLC) and eosinophil counts (REC) and pattern of distant metastasis, has been recently proposed for pembrolizumab-treated patients. Here, we applied this model to advanced melanoma patients receiving chemotherapy (n = 116) or anti-CTLA-4 therapy (n = 128). Visceral involvement, LDH and RLC were associated with prognosis regardless of treatment...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29104763/cardiotoxicity-of-immune-checkpoint-inhibitors
#10
REVIEW
Gilda Varricchi, Maria Rosaria Galdiero, Giancarlo Marone, Gjada Criscuolo, Maria Triassi, Domenico Bonaduce, Gianni Marone, Carlo Gabriele Tocchetti
Cardiac toxicity after conventional antineoplastic drugs (eg, anthracyclines) has historically been a relevant issue. In addition, targeted therapies and biological molecules can also induce cardiotoxicity. Immune checkpoint inhibitors are a novel class of anticancer drugs, distinct from targeted or tumour type-specific therapies. Cancer immunotherapy with immune checkpoint blockers (ie, monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand (PD-L1)) has revolutionised the management of a wide variety of malignancies endowed with poor prognosis...
2017: ESMO Open
https://www.readbyqxmd.com/read/29090224/production-and-evaluation-of-specific-single-chain-antibodies-against-ctla-4-for-cancer-targeted-therapy
#11
Farideh Hosseinzadeh, Saeed Mohammadi, Foroogh Nejatollahi
BACKGROUND: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecules are expressed on T-cells and inhibit their function by inhibiting activation of subsequent T-cell molecular pathways. Blocking of CTLA-4 inhibits the growth of malignant tumor cells. Anti-CTLA-4 monoclonal antibodies activate the immune system against cancer. Due to several advantages of single-chain antibodies (scFvs) compared to monoclonal antibodies in cancer immunotherapy, specific anti-CTLA-4 scFvs (single-chain variable fragment) were selected in this study...
October 2017: Reports of Biochemistry & Molecular Biology
https://www.readbyqxmd.com/read/29079654/characterization-of-thyroid-disorders-in-patients-receiving-immune-checkpoint-inhibition-therapy
#12
Hyunju Lee, F Stephen Hodi, Anita Giobbie-Hurder, Patrick A Ott, Elizabeth I Buchbinder, Rizwan Haq, Sara Tolaney, Romualdo Barroso-Sousa, Kevin Zhang, Hilary Donahue, Meredith Davis, Maria E Gargano, Kristina M Kelley, Rona S Carroll, Ursula B Kaiser, Le Min
Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder...
October 27, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29066909/case-report-of-a-kit-mutated-melanoma-patient-with-an-excellent-response-to-apatinib-and-temozolomide-combination-therapy
#13
Cong Luo, Jiayu Shen, Jieer Ying, Xianhua Fang, Xiaohong Wang, Zhixuan Fu, Peng Liu
Malignant melanoma is one kind of malignant disease which has high rates of mortality, metastasis, and poor prognosis. The therapeutic landscape is rapidly changing with the development of novel agents in recent decades, such as anti-PD-1 agents, anti-CTLA-4 agents, and BRAF inhibitors. However, since most of these novel agents are very expensive, not all patients can afford them. Apatinib is a novel oral small-molecule tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2) and may also be effective on Ret, c-KIT, and c-src...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29061217/-a-reflection-of-the-new-wave-of-immunotherapy-on-the-clinical-study-of-%C3%A2-chinese-lung-cancer-immunotherapy
#14
Jingjing Liu, Shuang Zhang, Shuang Li, Ying Cheng
Starting from the success of anti-CTLA-4 antibody in malignant melanoma, targeted immunotherapy has become one of the effective strategies for anti-tumor therapy, and raised a new wave of research on tumor immunotherapy. In the field of lung cancer, a series of clinical studies on immune-targeted drugs have been carried out aboard, nivolumab, pembrolizumab and atezolizumab have been approved for the treatment of lung cancer, which rewrite the history of lung cancer treatment. In China, clinical studies on immune-targeted drugs for lung cancer have also been developed...
October 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/29051489/genomic-landscape-associated-with-potential-response-to-anti-ctla-4-treatment-in-cancers
#15
Chan-Young Ock, Jun-Eul Hwang, Bhumsuk Keam, Sang-Bae Kim, Jae-Jun Shim, Hee-Jin Jang, Sarang Park, Bo Hwa Sohn, Minse Cha, Jaffer A Ajani, Scott Kopetz, Keun-Wook Lee, Tae Min Kim, Dae Seog Heo, Ju-Seog Lee
Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it...
October 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29045560/inflammatory-gastrointestinal-diseases-associated-with-pd-1-blockade-antibodies
#16
M Collins, J M Michot, F X Danlos, C Mussini, E Soularue, C Mateus, D Loirat, A Buisson, I Rosa, O Lambotte, S Laghouati, N Chaput, C Coutzac, A L Voisin, J C Soria, A Marabelle, S Champiat, C Robert, F Carbonnel
Background: Immune check-point blockade agents have shown clinical activity in cancer patients but are associated with immune-related adverse events that could limit their development. The aim of this study was to describe the gastrointestinal immune-related adverse events (GI-irAE) in patients with cancer treated with anti-PD-1. Methods: this is a retrospective study of consecutive adult patients who had a suspected GI-irAE due to anti-PD-1 antibodies between 2013 and 2016...
November 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29045547/safety-of-resuming-anti-pd-1-in-patients-with-immune-related-adverse-events-iraes-during-combined-anti-ctla-4-and-anti-pd1-in-metastatic-melanoma
#17
M H Pollack, A Betof, H Dearden, K Rapazzo, I Valentine, A S Brohl, K K Ancell, G V Long, A M Menzies, Z Eroglu, D B Johnson, A N Shoushtari
Background: Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and Methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs...
October 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29044660/real-world-treatment-patterns-and-outcomes-among-metastatic-cutaneous-melanoma-patients-treated-with-ipilimumab
#18
P M Mohr, P A Ascierto, A A Arance, G M McArthur, A H Hernaez, P K Kaskel, R S Shinde, K S Stevinson
BACKGROUND: There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011. OBJECTIVE: To evaluate ipilimumab and post-ipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain following regulatory approval. METHODS: Retrospective multicentre, multinational, observational chart review study...
October 17, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28987965/emerging-targets-in-cancer-immunotherapy
#19
REVIEW
Samantha Burugu, Amanda R Dancsok, Torsten O Nielsen
The first generation of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1) targeted natural immune homeostasis pathways, co-opted by cancers, to drive anti-tumor immune responses. These agents led to unprecedented results in patients with previously incurable metastatic disease and may become first-line therapies for some advanced cancers. However, these agents are efficacious in only a minority of patients. Newer strategies are becoming available that target additional immunomodulatory mechanisms to activate patients' own anti-tumor immune responses...
October 5, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28978021/remarkably-similar-ctla-4-binding-properties-of-therapeutic-ipilimumab-and-tremelimumab-antibodies
#20
Mengnan He, Yan Chai, Jianxun Qi, Catherine W H Zhang, Zhou Tong, Yi Shi, Jinghua Yan, Shuguang Tan, George F Gao
Monoclonal antibody based immune checkpoint blockade therapies have achieved clinical successes in management of malignant tumors. As the first monoclonal antibody targeting immune checkpoint molecules entered into clinics, the molecular basis of ipilimumab-based anti-CTLA-4 blockade has not yet been fully understood. In the present study, we report the complex structure of ipilimumab and CTLA-4. The complex structure showed similar contributions from VH and VL of ipilimumab in binding to CTLA-4 front β-sheet strands...
September 15, 2017: Oncotarget
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