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https://www.readbyqxmd.com/read/28811974/ex-vivo-assessment-of-drug-response-on-breast-cancer-primary-tissue-with-preserved-microenvironments
#1
Manuele G Muraro, Simone Muenst, Valentina Mele, Luca Quagliata, Giandomenica Iezzi, Alexandar Tzankov, Walter P Weber, Giulio C Spagnoli, Savas D Soysal
Interaction between cancerous, non-transformed cells, and non-cellular components within the tumor microenvironment plays a key role in response to treatment. However, short-term culture or xenotransplantation of cancer specimens in immunodeficient animals results in dramatic modifications of the tumor microenvironment, thus preventing reliable assessment of compounds or biologicals of potential therapeutic relevance. We used a perfusion-based bioreactor developed for tissue engineering purposes to successfully maintain the tumor microenvironment of freshly excised breast cancer tissue obtained from 27 breast cancer patients and used this platform to test the therapeutic effect of antiestrogens as well as checkpoint-inhibitors on the cancer cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28810147/macrophage-polarization-contributes-to-glioblastoma-eradication-by-combination-immunovirotherapy-and-immune-checkpoint-blockade
#2
Dipongkor Saha, Robert L Martuza, Samuel D Rabkin
Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Δ expressing murine IL-12 (G47Δ-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Δ-mIL12 cured most mice in two glioma models...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28810141/a-viro-immunotherapy-triple-play-for-the-treatment-of-glioblastoma
#3
John C Bell, Carolina S Ilkow
In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics.
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28808483/therapeutic-immune-monitoring-of-cd4-cd25-t-cells-in-chronic-myeloid-leukemia-patients-treated-with-tyrosine-kinase-inhibitors
#4
Ziyuan Lu, Na Xu, Xuan Zhou, Guanlun Gao, Lin Li, Jixian Huang, Yuling Li, Qisi Lu, Bolin He, Chengyun Pan, Xiaoli Liu
Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4(+)CD25(+) T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15)...
August 2017: Oncology Letters
https://www.readbyqxmd.com/read/28807491/adenosine-a2a-receptor-signaling-affects-il-21-il-22-cytokines-and-gata3-t-bet-transcription-factor-expression-in-cd4-t-cells-from-a-btbr-t-itpr3tf-j-mouse-model-of-autism
#5
Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Mashal M Almutairi, Sabry M Attia
Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T(+) Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders...
August 9, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28807052/whole-blood-rna-transcript-based-models-can-predict-clinical-response-in-two-large-independent-clinical-studies-of-patients-with-advanced-melanoma-treated-with-the-checkpoint-inhibitor-tremelimumab
#6
Philip Friedlander, Karl Wassmann, Alan M Christenfeld, David Fisher, Chrisann Kyi, John M Kirkwood, Nina Bhardwaj, William K Oh
BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions. METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#7
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28806575/lessons-from-ctla-4-deficiency-and-checkpoint-inhibition
#8
REVIEW
Bernice Lo, Ussama M Abdel-Motal
CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions...
August 11, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28803728/distinct-cellular-mechanisms-underlie-anti-ctla-4-and-anti-pd-1-checkpoint-blockade
#9
Spencer C Wei, Jacob H Levine, Alexandria P Cogdill, Yang Zhao, Nana-Ama A S Anang, Miles C Andrews, Padmanee Sharma, Jing Wang, Jennifer A Wargo, Dana Pe'er, James P Allison
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations...
August 9, 2017: Cell
https://www.readbyqxmd.com/read/28799876/melanoma-brain-metastasis-the-impact-of-stereotactic-radiosurgery-braf-mutational-status-and-targeted-and-or-immune-based-therapies-on-treatment-outcome
#10
Rupesh Kotecha, Jacob A Miller, Vyshak A Venur, Alireza M Mohammadi, Samuel T Chao, John H Suh, Gene H Barnett, Erin S Murphy, Pauline Funchain, Jennifer S Yu, Michael A Vogelbaum, Lilyana Angelov, Manmeet S Ahluwalia
OBJECTIVE The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM). METHODS A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAF (mut) and 43 had BRAF wild-type ( BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk...
August 11, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28797000/new-molecular-biological-and-immunological-agents-inducing-hypophysitis
#11
Anna Angelousi, Eleftherios Chatzellis, Gregory Kaltsas
<br>Hypophysitis is a relatively rare disease that exerts a strong autoimmune component encompassing different aetiologies. Immunomodulatory drugs, such as interferon-α, are known to rarely induce hypophysitis. In recent years a large number of new biological and immunomodulatory agents have been introduced into clinical practice. Although immune suppressing agents used for the treatment of autoimmune disorders only rarely are associated with hypophysitis, it is commonly encountered with immunomodulatory agents used for the treatment of cancer...
August 8, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28781967/immunotherapeutic-strategies-for-gastric-carcinoma-a-review-of-preclinical-and-clinical-recent-development
#12
REVIEW
Mohamed Abozeid, Antonio Rosato, Roberta Sommaggio
Gastric carcinoma (GC) is the 2nd most common cause of cancer-related death. Despite advances in conventional treatment and surgical interventions, a high percentage of GC patients still have poor survival. Recently, immunotherapy has become a promising approach to treat GC. Here, we present preclinical and clinical studies encouraging the use of vaccination, adoptive T-cell therapy (ACT), and immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28776731/correlations-of-ctla-4-exon-1-49-a-g-and-promoter-region-318%C3%A2-c-t-polymorphisms-with-the-therapeutic-efficacy-of-131-i-radionuclide-in-graves-disease-in-chinese-han-population
#13
Xin-Rui Han, Xin Wen, Shan Wang, Shao-Hua Fan, Juan Zhuang, Yong-Jian Wang, Zi-Feng Zhang, Meng-Qiu Li, Bin Hu, Qun Shan, Chun-Hui Sun, Ya-Xing Bao, Sha Luan, Chang-Jiu Zhao, Dong-Mei Wu, Jun Lu, Yuan-Lin Zheng
This study aimed to investigate the correlation of CTLA-4 exon-1 49 A/G and promoter region-318 C/T polymorphisms with the therapeutic efficacy of radionuclide (131) I for Graves' disease in Chinese Han population. The (131) I radionuclide therapy was applied in 261 patients with Graves' disease. The patients were classified into the remission and non-remission groups. PCR-RFLP was implemented to detect CTLA-4 exon-1 49 A/G and promoter region-318 C/T polymorphisms. Haplotypes of CTLA-4 49 A/G and -318 C/T were analyzed using SHEsis software online...
August 4, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28771750/comprehensive-t-cell-immunophenotyping-and-next-generation-sequencing-from-hpv-positive-and-negative-head-and-neck-squamous-cell-carcinomas
#14
Kate Poropatich, Joel Fontanarosa, Suchitra Swaminathan, Dave Dittmann, Siqi Chen, Sandeep Samant, Bin Zhang
The success of PD-1 inhibition in achieving a clinical response in a subset of HNSCC patients emphasizes the need to better understand the immunobiology of head and neck squamous cell carcinomas (HNSCC). Immunophenotyping was performed on 30 patients with HNSCC (16 HPV-positive, 14 HPV-negative) from matched tissue from the primary tumor site, locally metastatic cervical lymph nodes (LN), uninvolved local cervical LN and peripheral blood. CD4(+) and CD8(+) T cell lymphocytes obtained from tissue were analyzed for expression levels of inhibitory receptors PD-1, TIM-3 and CTLA-4...
August 3, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28771603/expression-of-pd-l1-and-other-immunotherapeutic-targets-in-thymic-epithelial-tumors
#15
Kathryn C Arbour, Jarushka Naidoo, Keith E Steele, Ai Ni, Andre L Moreira, Natasha Rekhtman, Paul B Robbins, Joyson Karakunnel, Andreas Rimner, James Huang, Gregory J Riely, Matthew D Hellmann
INTRODUCTION: The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs...
2017: PloS One
https://www.readbyqxmd.com/read/28770166/genomic-signature-of-the-natural-oncolytic-herpes-simplex-virus-hf10-and-its-therapeutic-role-in-preclinical-and-clinical-trials
#16
REVIEW
Ibrahim Ragab Eissa, Yoshinori Naoe, Itzel Bustos-Villalobos, Toru Ichinose, Maki Tanaka, Wu Zhiwen, Nobuaki Mukoyama, Taishi Morimoto, Noriyuki Miyajima, Hasegawa Hitoki, Seiji Sumigama, Branko Aleksic, Yasuhiro Kodera, Hideki Kasuya
Oncolytic viruses (OVs) are opening new possibilities in cancer therapy with their unique mechanism of selective replication within tumor cells and triggering of antitumor immune responses. HF10 is an oncolytic herpes simplex virus-1 with a unique genomic structure that has non-engineered deletions and insertions accompanied by frame-shift mutations, in contrast to the majority of engineered OVs. At the genetic level, HF10 naturally lacks the expression of UL43, UL49.5, UL55, UL56, and latency-associated transcripts, and overexpresses UL53 and UL54...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28768723/lamtor1-is-critically-required-for-cd4-t-cell-proliferation-and-regulatory-t-cell-suppressive-function
#17
Takashi Hosokawa, Tetsuya Kimura, Shigeyuki Nada, Tatsusada Okuno, Daisuke Ito, Sujin Kang, Satoshi Nojima, Kazuya Yamashita, Takeshi Nakatani, Yoshitomo Hayama, Yasuhiro Kato, Yuhei Kinehara, Masayuki Nishide, Norihisa Mikami, Syohei Koyama, Hyota Takamatsu, Daisuke Okuzaki, Naganari Ohkura, Shimon Sakaguchi, Masato Okada, Atsushi Kumanogoh
Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4(+) T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4(+) T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes...
August 2, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28768162/structural-biology-of-the-immune-checkpoint-receptor-pd-1-and-its-ligands-pd-l1-pd-l2
#18
REVIEW
Krzysztof M Zak, Przemyslaw Grudnik, Katarzyna Magiera, Alexander Dömling, Grzegorz Dubin, Tad A Holak
Cancer cells can avoid and suppress immune responses through activation of inhibitory immune checkpoint proteins, such as PD-1, PD-L1, and CTLA-4. Blocking the activities of these proteins with monoclonal antibodies, and thus restoring T cell function, has delivered breakthrough therapies against cancer. In this review, we describe the latest work on structural characterization of the checkpoint proteins, their interactions with cognate ligands and with therapeutic antibodies. Structures of the extracellular portions of these proteins reveal that they all have a similar modular structure, composed of small domains similar in topology to the domains found in antibodies...
August 1, 2017: Structure
https://www.readbyqxmd.com/read/28766553/regulatory-t-cells-with-superior-immunosuppressive-capacity-emigrate-from-the-inflamed-colon-to-draining-lymph-nodes
#19
Y Nakanishi, R Ikebuchi, T Chtanova, Y Kusumoto, H Okuyama, T Moriya, T Honda, K Kabashima, T Watanabe, Y Sakai, M Tomura
Foxp3(+) Regulatory T cells (Tregs) play a critical role in the maintenance of colon homeostasis. Here we utilized photoconvertible KikGR mice to track immune cells from the caecum and ascending (proximal) colon in the steady state and DSS-induced colitis. We found that Tregs from the proximal colon (colonic migratory Tregs) migrated exclusively to the distal part of mesenteric lymph nodes (dMLN) in an S1PR1-dependent process. In the steady state, colonic migratory CD25(+) Tregs expressed higher levels of CD103, ICOS, LAG3 and CTLA-4 in comparison with pre-existing LN Tregs...
August 2, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28763794/targeting-latency-associated-peptide-promotes-antitumor-immunity
#20
Galina Gabriely, Andre P da Cunha, Rafael M Rezende, Brendan Kenyon, Asaf Madi, Tyler Vandeventer, Nathaniel Skillin, Stephen Rubino, Lucien Garo, Maria A Mazzola, Panagiota Kolypetri, Amanda J Lanser, Thais Moreira, Ana Maria C Faria, Hans Lassmann, Vijay Kuchroo, Gopal Murugaiyan, Howard L Weiner
Regulatory T cells (Tregs) promote cancer by suppressing antitumor immune responses. We found that anti-LAP antibody, which targets the latency-associated peptide (LAP)/transforming growth factor-β (TGF-β) complex on Tregs and other cells, enhances antitumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma, and glioblastoma. Anti-LAP decreases LAP(+) Tregs, tolerogenic dendritic cells, and TGF-β secretion and is associated with CD8(+) T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8(+) T cells and reduces CD103(+) CD8 T cells in draining lymph nodes and the spleen...
May 19, 2017: Science Immunology
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