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https://www.readbyqxmd.com/read/28931755/combination-central-tolerance-and-peripheral-checkpoint-blockade-unleashes-antimelanoma-immunity
#1
Pearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K Hong, Imran Khan, Maria Mouchess, Ajay S Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M Kirkwood, Stergios Moschos, Lawrence Fong, Mark S Anderson, Maureen A Su
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28928380/predictors-of-responses-to-immune-checkpoint-blockade-in-advanced-melanoma
#2
N Jacquelot, M P Roberti, D P Enot, S Rusakiewicz, N Ternès, S Jegou, D M Woods, A L Sodré, M Hansen, Y Meirow, M Sade-Feldman, A Burra, S S Kwek, C Flament, M Messaoudene, C P M Duong, L Chen, B S Kwon, A C Anderson, V K Kuchroo, B Weide, F Aubin, C Borg, S Dalle, O Beatrix, M Ayyoub, B Balme, G Tomasic, A M Di Giacomo, M Maio, D Schadendorf, I Melero, B Dréno, A Khammari, R Dummer, M Levesque, Y Koguchi, L Fong, M Lotem, M Baniyash, H Schmidt, I M Svane, G Kroemer, A Marabelle, S Michiels, A Cavalcanti, M J Smyth, J S Weber, A M Eggermont, L Zitvogel
Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28926891/-advances-in-immune-checkpoint-inhibitors-in-gastrointestinal-cancer
#3
X R Zhu, L Z Zheng
Currently, immunotherapy is considered as the fourth major modality of cancer treatment except surgery, chemotherapy and radiotherapy. The new therapeutic approach based on immune checkpoint inhibitors is a landmark innovation. Strategies considering checkpoint inhibitors have shown good anti-tumor effect by targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1). Moreover, DNA mismatch repair-deficient tumors appear to be potential candidates for these therapies...
September 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28926356/development-of-bell-s-palsy-after-treatment-with-ipilimumab-and-nivolumab-for-metastatic-melanoma-a-case-report
#4
Julia M Zecchini, Sara Kim, Kendra Yum, Philip Friedlander
Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face...
September 18, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28920006/dosing-immunotherapy-combinations-analysis-of-3-526-patients-for-toxicity-and-response-patterns
#5
Mina Nikanjam, Harsh Patel, Razelle Kurzrock
Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28920005/the-frequency-of-neoantigens-per-somatic-mutation-rather-than-overall-mutational-load-or-number-of-predicted-neoantigens-per-se-is-a-prognostic-factor-in-ovarian-clear-cell-carcinoma
#6
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28920002/ep4-antagonism-by-e7046-diminishes-myeloid-immunosuppression-and-synergizes-with-treg-reducing-il-2-diphtheria-toxin-fusion-protein-in-restoring-anti-tumor-immunity
#7
Diana I Albu, Zichun Wang, Kuan-Chun Huang, Jiayi Wu, Natalie Twine, Sarah Leacu, Christy Ingersoll, Lana Parent, Winnie Lee, Diana Liu, Renee Wright-Michaud, Namita Kumar, Galina Kuznetsov, Qian Chen, Wanjun Zheng, Kenichi Nomoto, Mary Woodall-Jappe, Xingfeng Bao
Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919997/increased-infiltration-and-tolerised-antigen-specific-cd8-tem-cells-in-tumor-but-not-peripheral-blood-have-no-impact-on-survival-of-hcmv-glioblastoma-patients
#8
M Bahador, A Gras Navarro, M A Rahman, M Dominguez-Valentin, S Sarowar, E Ulvestad, G Njølstad, S A Lie, E K Kristoffersen, E Bratland, M Chekenya
Human cytomegalovirus (HCMV) antigens in glioblastoma (GBM) present opportunities for personalised immunotherapy. However, their presence in GBM tissue is still under debate, and evidence of their impact on functional immune responses and prognosis is sparse. Here, we investigated the presence of pp65 (UL83) and immediate early 1 (IE-1) HCMV antigens in a cohort of Norwegian GBM patients (n = 177), using qPCR, immunohistochemistry, and serology. HCMV status was then used to investigate whether viral antigens influenced immune cell phenotype, infiltration, activation and patient survival...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919585/association-of-human-leukocyte-antigens-class-i-and-ii-with-graves-disease-in-iranian-population
#9
Zahra Mehraji, Ali Farazmand, Alireza Esteghamati, Sina Noshad, Maryam Sadr, Somayeh Amirzargar, Mir Saeed Yekaninejad, Aliakbar Amirzargar
BACKGROUND: Graves' disease (GD), a highly rampant autoimmune disorder of the thyroid gland, is responsible for 60-80% of the clinical cases of hyperthyroidism. Over the past decades, genetic association studies have identified several GD susceptibility loci in CTLA-4, TSHR and major histocompatibility complex regions. The information on the association between the human leukocyte antigens (HLA) and GD among Iranians is scarce. OBJECTIVE: To identify HLA polymorphisms that might confer susceptibility or protect against GD...
September 2017: Iranian Journal of Immunology: IJI
https://www.readbyqxmd.com/read/28918052/a-ctla-4-antagonizing-dna-aptamer-with-antitumor-effect
#10
Bo-Tsang Huang, Wei-Yun Lai, Yi-Chung Chang, Jen-Wei Wang, Shauh-Der Yeh, Emily Pei-Ying Lin, Pan-Chyr Yang
The successful translation of cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade has revolutionized the concept of cancer immunotherapy. Although monoclonal antibody therapeutics remain the mainstream in clinical practice, aptamers are synthetic oligonucleotides that encompass antibody-mimicking functions. Here, we report a novel high-affinity CTLA-4-antagonizing DNA aptamer (dissociation constant, 11.84 nM), aptCTLA-4, which was identified by cell-based SELEX and high-throughput sequencing. aptCTLA-4 is relatively stable in serum, promotes lymphocyte proliferation, and inhibits tumor growth in cell and animal models...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28916749/checkpoint-blockade-immunotherapy-reshapes-the-high-dimensional-phenotypic-heterogeneity-of-murine-intratumoural-neoantigen-specific-cd8-t-cells
#11
M Fehlings, Y Simoni, H L Penny, E Becht, C Y Loh, M M Gubin, J P Ward, S C Wong, R D Schreiber, E W Newell
The analysis of neoantigen-specific CD8(+) T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8(+) T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28915554/resistance-to-ctla-4-checkpoint-inhibition-reversed-through-selective-elimination-of-granulocytic-myeloid-cells
#12
Paul E Clavijo, Ellen C Moore, Jianhong Chen, Ruth J Davis, Jay Friedman, Young Kim, Carter Van Waes, Zhong Chen, Clint T Allen
PURPOSE: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. EXPERIMENTAL DESIGN: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914644/systemic-therapy-in-advanced-melanoma-integrating-targeted-therapy-and-immunotherapy-into-clinical-practice
#13
Inês P Silva, Georgina V Long
PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable...
September 12, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28912267/antitumor-immunity-is-defective-in-t-cell-specific-microrna-155-deficient-mice-and-is-rescued-by-immune-checkpoint-blockade
#14
Thomas B Huffaker, Soh-Hyun Lee, William W Tang, Jared A Wallace, Margaret Alexander, Marah C Runtsch, Dane K Larsen, Jacob Thompson, Andrew G Ramstead, Warren P Voth, Ruozhen Hu, June L Round, Matthew A Williams, Ryan M O'Connell
MicroRNA-155 (miR-155) regulates antitumor immune responses. However, its specific functions within distinct immune cell types have not been delineated in conditional knockout (KO) mouse models. In this study, we investigated the role of miR-155 specifically within T cells during the immune response to syngeneic tumors. We found that miR-155 expression within T cells is required to limit syngeneic tumor growth and promote interferon gamma (IFNγ) production by T cells within the tumor microenvironment. Consequently, we found that miR-155 expression by T cells is necessary for proper tumor-associated macrophage (TAM) expression of IFNγ-inducible genes...
September 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28904197/differential-inhibitory-receptor-expression-on-t-cells-delineates-functional-capacities-in-chronic-viral-infection
#15
Jeffrey E Teigler, Gennadiy Zelinskyy, Michael A Eller, Diane L Bolton, Mary Marovich, Alexander D Gordon, Aljawharah Alrubayyi, Galit Alter, Merlin L Robb, Jeffrey N Martin, Steven G Deeks, Nelson L Michael, Ulf Dittmer, Hendrik Streeck
Inhibitory receptors have been extensively described for their importance in regulating immune responses in chronic infections and cancers. Blocking the function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 have shown promise for augmenting CD8 T cell activity and boosting pathogen-specific immunity. However, the prevalence of inhibitory receptors on CD4 T cells and their relative influence on CD4 T cell functionality in chronic HIV infection remains poorly described. We therefore determined and compared inhibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus-specific CD4 and CD8 T cells in relation to their functional T cell profile...
September 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28903456/tumor-reductive-therapies-and-antitumor-immunity
#16
REVIEW
Huiqin Guo, Kangla Tsung
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901560/erythema-nodosum-like-panniculitis-mimicking-disease-recurrence-a-novel-toxicity-from-immune-checkpoint-blockade-therapy-report-of-two-patients
#17
Michael T Tetzlaff, Amir A Jazaeri, Carlos A Torres-Cabala, Brinda Rao Korivi, Genie A Landon, Priyadharsini Nagarajan, Adrienne Choksi, Leon Chen, Marc Uemura, Phyu P Aung, Adi Diab, Padmanee Sharma, Michael A Davies, Rodabe Amaria, Victor G Prieto, Jonathan L Curry
Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have demonstrated substantial clinical benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases...
September 13, 2017: Journal of Cutaneous Pathology
https://www.readbyqxmd.com/read/28900984/-targeted-therapy-combined-with-immunotherapy-in-gastrointestinal-stromal-tumor-a-new-era-of-hope-and-challenges
#18
Wenyi Zhao, Hui Cao
New immunotherapy represented by immune checkpoint inhibitor therapy and chimeric antigen receptor T-Cell immunotherapy (CAR-T) has already become hot trend in the treatment of malignant tumors. In gastrointestinal stromal tumor (GIST), with notable tumor-infiltrating immune cells existing in GIST tissues and immunological effects reported in imatinib mesylate (IM) treatment, the clinicians and researchers started to realize the possibilities of immunotherapy in GIST. Recent studies reported that PD-1/PD-L1 or CTLA-4 blockade may enhance the T-cell activity and anti-tumor effect of targeted therapy, which can be applied in advanced GIST, and anti-KIT CAR T-cells indicated a new immunotherapeutic targeted strategy for GIST patients with TKI resistance...
September 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28900679/ctla-4-an-essential-immune-checkpoint-for-t-cell-activation
#19
Shunsuke Chikuma
The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28894725/safety-of-checkpoint-inhibitors-for-cancer-treatment-strategies-for-patient-monitoring-and-management-of-immune-mediated-adverse-events
#20
REVIEW
Marianne Davies, Emily A Duffield
Immune checkpoint inhibitors (ICPIs), in the form of monoclonal antibodies against CTLA-4, PD-1, and PD-L1, have dramatically changed the treatment approach in several advanced cancers. Due to their mechanism of action, these novel agents are associated with a unique spectrum of immune-mediated adverse events (imAEs), with a safety profile that indicates they are better tolerated than traditional chemotherapeutic agents. This article aims to provide education on the current knowledge about imAEs associated with ICPI treatment, including strategies and tools for the prompt identification, evaluation, and optimal management of these events...
2017: ImmunoTargets and Therapy
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