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https://www.readbyqxmd.com/read/29773326/tremelimumab-combined-with-durvalumab-in-patients-with-mesothelioma-nibit-meso-1-an-open-label-non-randomised-phase-2-study
#1
Luana Calabrò, Aldo Morra, Diana Giannarelli, Giovanni Amato, Armida D'Incecco, Alessia Covre, Arthur Lewis, Marlon C Rebelatto, Riccardo Danielli, Maresa Altomonte, Anna Maria Di Giacomo, Michele Maio
BACKGROUND: Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. METHODS: In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses...
May 14, 2018: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/29770915/cytolytic-activity-score-to-assess-anticancer-immunity-in-colorectal-cancer
#2
Sumana Narayanan, Tsutomu Kawaguchi, Li Yan, Xuan Peng, Qianya Qi, Kazuaki Takabe
BACKGROUND: Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity. METHODS: Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA)...
May 16, 2018: Annals of Surgical Oncology
https://www.readbyqxmd.com/read/29769148/current-landscape-and-future-of-dual-anti-ctla4-and-pd-1-pd-l1-blockade-immunotherapy-in-cancer-lessons-learned-from-clinical-trials-with-melanoma-and-non-small-cell-lung-cancer-nsclc
#3
REVIEW
Young Kwang Chae, Ayush Arya, Wade Iams, Marcelo R Cruz, Sunandana Chandra, Jaehyuk Choi, Francis Giles
Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens...
May 16, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29762907/genetic-differences-between-type-1-diabetes-with-and-without-other-autoimmune-diseases
#4
Kanako Shimura, Junnosuke Miura, Manabu Kawamoto, Yasushi Kawaguchi, Hisashi Yamanaka, Yasuko Uchigata
BACKGROUND: Clusters of autoimmune diseases (ADs) are present in some people with type 1 diabetes. This clustering suggests the existence of common genetic backgrounds for abnormal autoimmunity in these individuals. However, the genetic differences between type 1 diabetes patients with and without other ADs are not well known. METHODS: To investigate the clinical background and genetic differences between type 1 diabetes patients with and without other ADs, SNPs in the CTLA4, SUMO4, PTPN22, IRF5, STAT4 and BLK genes were analyzed using either a TaqMan assay or direct sequencing...
May 15, 2018: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/29757192/cd155-loss-enhances-tumor-suppression-via-combined-host-and-tumor-intrinsic-mechanisms
#5
Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W Lane, Michele Wl Teng, William C Dougall, Mark J Smyth
Critical immune-suppressive pathways beyond programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) require greater attention. Nectins and nectin-like molecules might be promising targets for immunotherapy, since they play critical roles in cell proliferation and migration and exert immunomodulatory functions in pathophysiological conditions. Here, we show CD155 expression in both malignant cells and tumor-infiltrating myeloid cells in humans and mice. Cd155-/- mice displayed reduced tumor growth and metastasis via DNAM-1 upregulation and enhanced effector function of CD8+ T and NK cells, respectively...
May 14, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29743613/immune-quiescence-in-the-oral-mucosa-is-maintained-by-a-uniquely-large-population-of-highly-activated-foxp3-regulatory-t-cells
#6
Joo-Young Park, Hyunsoo Chung, Devon T DiPalma, Xuguang Tai, Jung-Hyun Park
The oral mucosa is a critical barrier tissue that protects the oral cavity against invading pathogens and foreign antigens. Interestingly, inflammation in the oral cavity is rarely observed, indicating that overt immune activation in this site is actively suppressed. Whether Foxp3+ Treg cells are involved in controlling immunity of the oral mucosa, however, is not fully understood. Here, we show that the oral mucosa is highly enriched in Foxp3+ Treg cells, and that oral mucosa Treg cells are phenotypically distinct from those of LN or spleen, as they expressed copious amounts of the tissue-retention molecule CD103 and unusually high-levels of CTLA4...
May 9, 2018: Mucosal Immunology
https://www.readbyqxmd.com/read/29739316/a-genome-wide-survey-of-mutations-in-the-jurkat-cell-line
#7
Louis Gioia, Azeem Siddique, Steven R Head, Daniel R Salomon, Andrew I Su
BACKGROUND: The Jurkat cell line has an extensive history as a model of T cell signaling. But at the turn of the 21st century, some expression irregularities were observed, raising doubts about how closely the cell line paralleled normal human T cells. While numerous expression deficiencies have been described in Jurkat, genetic explanations have only been provided for a handful of defects. RESULTS: Here, we report a comprehensive catolog of genomic variation in the Jurkat cell line based on whole-genome sequencing...
May 8, 2018: BMC Genomics
https://www.readbyqxmd.com/read/29731463/-diagnosis-and-treatment-of-rheumatoid-arthritis-toward-the-best-practice-best-practice-in-the-use-of-t-cell-co-stimulatory-inhibitor-for-patients-with-rheumatoid-arthritis
#8
Shinsuke Yasuda
CTLA4 abolishes interaction between CD28 on T cells and B7 molecules on antigen presenting cells. CTLA4-Ig, abatacept(ABT)was developed as a drug with multipotent inhibitor against activated T/B cells, monocytes, dendritic cells, macrophages and osteoclast progenitors expressing B7 molecules. In phase Ⅲ RCTs, clinical effects of ABT have been established in MTX-naive, MTX-IR and TNF inhibitor-IR patients with RA. Moreover, in head-to head comparison with representative TNF inhibitors, ABT exerted compatible clinical effect...
2018: Clinical Calcium
https://www.readbyqxmd.com/read/29729943/phenotype-penetrance-and-treatment-of-133-ctla-4-insufficient-individuals
#9
Charlotte Schwab, Annemarie Gabrysch, Peter Olbrich, Virginia Patiño, Klaus Warnatz, Daniel Wolff, Akihiro Hoshino, Masao Kobayashi, Kohsuke Imai, Masatoshi Takagi, Ingunn Dybedal, Jamanda A Haddock, David Sansom, Jose M Lucena, Maximilian Seidl, Annette Schmitt-Gräff, Veronika Reiser, Florian Emmerich, Natalie Frede, Alla Bulashevska, Ulrich Salzer, Desirée Schubert, Seiichi Hayakawa, Satoshi Okada, Maria Kanariou, Zeynep Yesim Kucuk, Hugo Chapdelaine, Lenka Petruzelkova, Zdenek Sumnik, Anna Sediva, Mary Slatter, Peter D Arkwright, Andrew Cant, Hanns-Martin Lorenz, Thomas Giese, Vassilios Lougaris, Alessandro Plebani, Christina Price, Kathleen E Sullivan, Michel Moutschen, Jiri Litzman, Tomas Freiberger, Frank L van de Veerdonk, Mike Recher, Michael H Albert, Fabian Hauck, Suranjith Seneviratne, Jana Pachlopnik Schmid, Antonios Kolios, Gary Unglik, Christian Klemann, Carsten Speckmann, Stephan Ehl, Alan Leichtner, Richard Blumberg, Andre Franke, Scott Snapper, Sebastian Zeissig, Charlotte Cunningham-Rundles, Lisa Giulino-Roth, Olivier Elemento, Gregor Dückers, Tim Niehues, Eva Fronkova, Veronika Kanderová, Craig D Platt, Janet Chou, Talal Chatila, Raif Geha, Elizabeth McDermott, Su Bunn, Monika Kurzai, Ansgar Schulz, Laia Alsina, Ferran Casals, Angela Deyà-Martinez, Sophie Hambleton, Hirokazu Kanegane, Kjetil Taskén, Olaf Neth, Bodo Grimbacher
BACKGROUND: Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in humans. OBJECTIVE: To characterize the penetrance, the clinical features and the best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcome of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers...
May 3, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29729581/immune-prophets-of-lung-cancer-the-prognostic-and-predictive-landscape-of-cellular-and-molecular-immune-markers
#10
REVIEW
Ivana Catacchio, Anna Scattone, Nicola Silvestris, Anita Mangia
Lung cancer is the leading cause of cancer deaths throughout the world. The majority of patients are diagnosed with locally advanced or metastatic disease when surgery, the best curative option, is no longer feasible. Thus, the prognosis of lung cancer remains poor and heterogeneous and new biomarkers are needed. As the immune system plays a pivotal role in cancer, the study of tumor microenvironment, with regard to the immune component, may provide valuable information for a better comprehension of the pathogenesis and progression of the disease...
May 2, 2018: Translational Oncology
https://www.readbyqxmd.com/read/29722117/upregulation-of-cd80-on-glomerular-podocytes-plays-an-important-role-in-development-of-proteinuria-following-pig-to-baboon-xeno-renal-transplantation-an-experimental-study
#11
Christopher J Rivard, Tatsu Tanabe, Miguel A Lanaspa, Hironosuke Watanabe, Shunichiro Nomura, Ana Andres-Hernando, Krystle Garth, Mitsuhiro Sekijima, Takuji Ishimoto, Yuichi Ariyoshi, Gabriela E Garcia, Jigesh Shah, Lennan Boyd, Masayuki Tasaki, Thomas Pomposelli, Akira Shimizu, David H Sachs, Richard J Johnson, Kazuhiko Yamada
We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1, 3-galactosyl transferase gene knockout pigs, with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy...
May 2, 2018: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/29721379/increased-immune-infiltration-and-chemokine-receptor-expression-in-head-and-neck-epithelial-tumors-after-neoadjuvant-immunotherapy-with-the-irx-2-regimen
#12
Neil L Berinstein, Michael McNamara, Ariane Nguyen, James Egan, Gregory T Wolf
IRX-2 is an injectable cancer immunotherapy composed of cytokines purified from stimulated normal-donor peripheral blood mononuclear cells. In a phase 2a trial (n = 27), neoadjuvant IRX-2 significantly increased lymphocyte infiltration (LI) into resected head and neck tumors and was associated with changes in fibrosis and necrosis. Event-free survival was 65% at 2 years, and overall survival 65% at 5 years. Overall survival was longer for patients with LI greater versus lower than the median. This substudy of the mechanisms responsible for the increase in LI with neoadjuvant IRX-2 employed multiplex immunohistochemistry (IHC) and transcriptome analysis to interrogate matched pre- and post-treatment tumor specimens from 7 available phase 2a trial patients...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29721371/complimentary-mechanisms-of-dual-checkpoint-blockade-expand-unique-t-cell-repertoires-and-activate-adaptive-anti-tumor-immunity-in-triple-negative-breast-tumors
#13
Erika J Crosby, Junping Wei, Xiao Yi Yang, Gangjun Lei, Tao Wang, Cong-Xiao Liu, Pankaj Agarwal, Alan J Korman, Michael A Morse, Kenneth Gouin, Simon R V Knott, H Kim Lyerly, Zachary C Hartman
Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29719630/genetic-susceptibility-to-bone-and-soft-tissue-sarcomas-a-field-synopsis-and-meta-analysis
#14
Clara Benna, Andrea Simioni, Sandro Pasquali, Davide De Boni, Senthilkumar Rajendran, Giovanna Spiro, Chiara Colombo, Calogero Virgone, Steven G DuBois, Alessandro Gronchi, Carlo Riccardo Rossi, Simone Mocellin
Background: The genetic architecture of bone and soft tissue sarcomas susceptibility is yet to be elucidated. We aimed to comprehensively collect and meta-analyze the current knowledge on genetic susceptibility in these rare tumors. Methods: We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing sarcomas through searching PubMed, The Cochrane Library, Scopus and Web of Science databases...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29712568/discovery-and-preclinical-characterization-of-the-antagonist-anti-pd-l1-monoclonal-antibody-ly3300054
#15
Yiwen Li, Carmine Carpenito, George Wang, David Surguladze, Amelie Forest, Maria Malabunga, Mary Murphy, Yiwei Zhang, Andreas Sonyi, Darin Chin, Douglas Burtrum, Ivan Inigo, Anthony Pennello, Leyi Shen, Laurent Malherbe, Xinlei Chen, Gerald Hall, Jaafar N Haidar, Dale L Ludwig, Ruslan D Novosiadly, Michael Kalos
BACKGROUND: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. RESULTS: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80...
April 30, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29710228/immune-profiling-of-premalignant-lesions-in-patients-with-lynch-syndrome
#16
Kyle Chang, Melissa W Taggart, Laura Reyes-Uribe, Ester Borras, Erick Riquelme, Reagan M Barnett, Guido Leoni, F Anthony San Lucas, Maria T Catanese, Federica Mori, Maria G Diodoro, Y Nancy You, Ernest T Hawk, Jason Roszik, Paul Scheet, Scott Kopetz, Alfredo Nicosia, Elisa Scarselli, Patrick M Lynch, Florencia McAllister, Eduardo Vilar
Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS...
April 16, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29708143/combination-immuno-oncology-therapy-with-immune-checkpoint-blockers-targeting-pd-l1-pd-1-or-ctla4-and-epigenetic-drugs-targeting-myc-and-immune-evasion-for-precision-medicine
#17
EDITORIAL
https://www.readbyqxmd.com/read/29705787/immune-checkpoint-inhibition-in-gastro-oesophageal-cancer
#18
Elizabeth Smyth, Peter C Thuss-Patience
Recently some progress has been made in the palliative treatment of gastric cancer. It was shown that second-line chemotherapy and VEGF-R2-directed treatment can prolong survival. Despite these advances most patients with metastatic gastric cancer live for less than 2 years. Immune-checkpoint blockade with anti-CTLA4, anti-PD-1 and anti-PD-L1 antibodies has revolutionised the treatment of many cancers. Significant benefit was also proven in gastric adenocarcinomas. Nivolumab improves overall survival as third-line treatment in Asian gastric cancer patients and is already registered in Japan...
2018: Oncology Research and Treatment
https://www.readbyqxmd.com/read/29705743/-in-vivo-visualisation-of-different-modes-of-action-of-biological-dmards-inhibiting-osteoclastic-bone-resorption
#19
Yoshinobu Matsuura, Junichi Kikuta, Yuika Kishi, Tetsuo Hasegawa, Daisuke Okuzaki, Toru Hirano, Masafumi Minoshima, Kazuya Kikuchi, Atsushi Kumanogoh, Masaru Ishii
OBJECTIVES: Osteoclasts play critical roles in inflammatory bone destruction. Precursor cell migration, cell differentiation, and functional cell activation are all in play. Biological disease-modifying antirheumatic drugs (DMARDs) have been shown to significantly inhibit both bone erosion as well as synovitis, although how such agents reduce osteoclastic bone destruction in vivo has not been fully explained. Here, we used an intravital time-lapse imaging technique to directly visualise mature osteoclasts and their precursors, and explored how different biological DMARDs acted in vivo ...
April 28, 2018: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/29695749/oncolytic-viruses-as-engineering-platforms-for-combination-immunotherapy
#20
REVIEW
Kwame Twumasi-Boateng, Jessica L Pettigrew, Y Y Eunice Kwok, John C Bell, Brad H Nelson
To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers...
April 25, 2018: Nature Reviews. Cancer
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