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https://www.readbyqxmd.com/read/28331616/ex-vivo-akt-inhibition-promotes-the-generation-of-potent-cd19car-t-cells-for-adoptive-immunotherapy
#1
Ryan Urak, Miriam Walter, Laura Lim, ChingLam W Wong, Lihua E Budde, Sandra Thomas, Stephen J Forman, Xiuli Wang
BACKGROUND: Insufficient persistence and effector function of chimeric antigen receptor (CAR)-redirected T cells have been challenging issues for adoptive T cell therapy. Generating potent CAR T cells is of increasing importance in the field. Studies have demonstrated the importance of the Akt pathway in the regulation of T cell differentiation and memory formation. We now investigate whether inhibition of Akt signaling during ex vivo expansion of CAR T cells can promote the generation of CAR T cells with enhanced antitumor activity following adoptive therapy in a murine leukemia xenograft model...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28289713/th17-cells-are-refractory-to-senescence-and-retain-robust-antitumor-activity-after-long-term-ex-vivo-expansion
#2
Jacob S Bowers, Michelle H Nelson, Kinga Majchrzak, Stefanie R Bailey, Baerbel Rohrer, Andrew D M Kaiser, Carl Atkinson, Luca Gattinoni, Chrystal M Paulos
Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8(+) T cells for treatment, they also cause decline in the cell's therapeutic fitness. In contrast, we discovered that IL-17-producing CD4(+) T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28258935/the-predominance-of-a-naive-t-helper-cell-subset-in-the-immune-response-of-experimental-acute-pancreatitis
#3
Andrea I Schmidt, Christian Kühlbrey, Robert Lauch, Guido Wolff-Vorbeck, Sophia Chikhladze, Ulrich T Hopt, Uwe A Wittel
INTRODUCTION: In necrotizing acute pancreatitis (NAP), systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS) decide overall outcome and mortality. In patients, low lymphocyte counts were found, but T-helper cells seemed to conversely increase. Our aim was to further categorize T-helper cells within the context of NAP induced SIRS and CARS. METHODS: NAP was induced by injection of sodium-taurocholate into the common bile duct of male BALB/c mice; sham treated animals received saline infusion...
February 22, 2017: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
https://www.readbyqxmd.com/read/28165340/targeting-the-adenosine-2a-receptor-enhances-chimeric-antigen-receptor-t-cell-efficacy
#4
Paul A Beavis, Melissa A Henderson, Lauren Giuffrida, Jane K Mills, Kevin Sek, Ryan S Cross, Alexander J Davenport, Liza B John, Sherly Mardiana, Clare Y Slaney, Ricky W Johnstone, Joseph A Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H Kershaw, Phillip K Darcy
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs)...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28153101/viral-vector-malaria-vaccines-induce-high-level-t-cell-and-antibody-responses-in-west-african-children-and-infants
#5
Carly M Bliss, Abdoulie Drammeh, Georgina Bowyer, Guillaume S Sanou, Ya Jankey Jagne, Oumarou Ouedraogo, Nick J Edwards, Casimir Tarama, Nicolas Ouedraogo, Mireille Ouedraogo, Jainaba Njie-Jobe, Amidou Diarra, Muhammed O Afolabi, Alfred B Tiono, Jean Baptiste Yaro, Uche J Adetifa, Susanne H Hodgson, Nicholas A Anagnostou, Rachel Roberts, Christopher J A Duncan, Riccardo Cortese, Nicola K Viebig, Odile Leroy, Alison M Lawrie, Katie L Flanagan, Beate Kampmann, Egeruan B Imoukhuede, Sodiomon B Sirima, Kalifa Bojang, Adrian V S Hill, Issa Nébié, Katie J Ewer
Heterologous prime-boosting with viral vectors encoding the pre-erythrocytic antigen thrombospondin-related adhesion protein fused to a multiple epitope string (ME-TRAP) induces CD8(+) T cell-mediated immunity to malaria sporozoite challenge in European malaria-naive and Kenyan semi-immune adults. This approach has yet to be evaluated in children and infants. We assessed this vaccine strategy among 138 Gambian and Burkinabe children in four cohorts: 2- to 6-year olds in The Gambia, 5- to 17-month-olds in Burkina Faso, and 5- to 12-month-olds and 10-week-olds in The Gambia...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28100832/reporter-gene-imaging-of-targeted-t-cell-immunotherapy-in-recurrent-glioma
#6
Khun Visith Keu, Timothy H Witney, Shahriar Yaghoubi, Jarrett Rosenberg, Anita Kurien, Rachel Magnusson, John Williams, Frezghi Habte, Jamie R Wagner, Stephen Forman, Christine Brown, Martin Allen-Auerbach, Johannes Czernin, Winson Tang, Michael C Jensen, Behnam Badie, Sanjiv S Gambhir
High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8(+) cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type 1 thymidine kinase (HSV1-TK) and interleukin-13 (IL-13) zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it would be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs...
January 18, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/27941285/basics-of-cancer-immunotherapy
#7
Yuki Fujioka, Hiroyoshi Nishikawa
The immune system is the body's defense against infectious organisms and other invaders including cancer cells. Cancer immunotherapy, which employs our own immune systems to attack cancer cells, is now emerging as a promising modality of cancer treatment based upon the clinical successes of immune checkpoint blockade and adoptive T cell transfer. In hematologic malignancies, clinical application of anti-PD-1 mAb and CAR (chimeric antigen receptor) T therapy is now being extensively tested in Hodgkin's disease, multiple myeloma, and CD19(+) acute lymphocytic leukemia...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27833058/basophil-mediated-pro-allergic-inflammation-in-vehicle-emitted-particles-exposure
#8
Alexander M Zakharenko, Ayse Basak Engin, Valery V Chernyshev, Vladimir V Chaika, Sergey M Ugay, Ramin Rezaee, Gholamreza Karimi, Vladimir A Drozd, Anna V Nikitina, Sergey F Solomennik, Olga R Kudryavkina, Liu Xin, Yuan Wenpeng, Manolis Tzatzarakis, Aristidis M Tsatsakis, Kirill S Golokhvast
Despite of the fact that engine manufacturers develop a new technology to reduce exhaust emissions, insufficient attention given to particulate emissions. However, diesel exhaust particles are a major source of air-borne pollution, contain vast amount of polycyclic aromatic hydrocarbons (PAHs) and may have deleterious effects on the immune system, resulting in the induction and enhancement of pro-allergic processes. In the current study, vehicle emitted particles (VEP) from 2 different types of cars (diesel - D and gasoline - G) and locomotive (L) were collected...
January 2017: Environmental Research
https://www.readbyqxmd.com/read/27784396/-effect-of-rbc-transfusion-on-t-lymphocyte-subsets-of-patients-with-hematologic-malignancies
#9
Fang Ye, Li-Ping Zhang
OBJECTIVE: To explore the effect of red blood cell(RBC) transfusion on T lymphocyte subsets in the patients with hematologic malignancies. METHODS: The patients admitted in department of hematology of the second hospital of Shanxi Medical University from September 2013 to September 2014 acconuted for 144 cases had been diagnosed with hematologic malignancies and needed RBC transfusions according to clinical transfusion creteria (Hb level<70 g/L). All the patients were in rest period after chemotherapy, furthermore they did not administrate immunomodulatory drugs...
October 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/27689397/a-cd22-reactive-tcr-from-the-t-cell-allorepertoire-for-the-treatment-of-acute-lymphoblastic-leukemia-by-tcr-gene-transfer
#10
Lorenz Jahn, Renate S Hagedoorn, Dirk M van der Steen, Pleun Hombrink, Michel G D Kester, Marjolein P Schoonakker, Daniëlle de Ridder, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk
CD22 is currently evaluated as a target-antigen for the treatment of B-cell malignancies using chimeric antigen receptor (CAR)-engineered T-cells or monoclonal antibodies (mAbs). CAR- and mAbs-based immunotherapies have been successfully applied targeting other antigens, however, occurrence of refractory disease to these interventions urges the identification of additional strategies. Here, we identified a TCR recognizing the CD22-derived peptide RPFPPHIQL (CD22RPF) presented in human leukocyte antigen (HLA)-B*07:02...
September 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27605551/immunotherapy-of-non-hodgkin-s-lymphoma-with-a-defined-ratio-of-cd8-and-cd4-cd19-specific-chimeric-antigen-receptor-modified-t-cells
#11
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Michael Hudecek, Barbara Pender, Emily Robinson, Reed Hawkins, Colette Chaney, Sindhu Cherian, Xueyan Chen, Lorinda Soma, Brent Wood, Daniel Li, Shelly Heimfeld, Stanley R Riddell, David G Maloney
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu)...
September 7, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27535056/chimeric-antigen-receptor-t-cells-guided-by-the-single-chain-fv-of-a-broadly-neutralizing-antibody-specifically-and-effectively-eradicate-virus-reactivated-from-latency-in-cd4-t-lymphocytes-isolated-from-hiv-1-infected-individuals-receiving-suppressive-combined
#12
Bingfeng Liu, Fan Zou, Lijuan Lu, Cancan Chen, Dalian He, Xu Zhang, Xiaoping Tang, Chao Liu, Linghua Li, Hui Zhang
Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology...
November 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27390347/preclinical-assessment-of-cd171-directed-car-t-cell-adoptive-therapy-for-childhood-neuroblastoma-ce7-epitope-target-safety-and-product-manufacturing-feasibility
#13
Annette Künkele, Agne Taraseviciute, Laura S Finn, Adam J Johnson, Carolina Berger, Olivia Finney, Cindy A Chang, Lisa S Rolczynski, Christopher Brown, Stephanie Mgebroff, Michael Berger, Julie R Park, Michael C Jensen
PURPOSE: The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)-redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. EXPERIMENTAL DESIGN: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays...
July 7, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27329987/a-tet-on-inducible-system-for-controlling-cd19-chimeric-antigen-receptor-expression-upon-drug-administration
#14
Reona Sakemura, Seitaro Terakura, Keisuke Watanabe, Jakrawadee Julamanee, Erina Takagi, Kotaro Miyao, Daisuke Koyama, Tatsunori Goto, Ryo Hanajiri, Tetsuya Nishida, Makoto Murata, Hitoshi Kiyoi
T cells genetically modified with a CD19 chimeric antigen receptor (CD19CAR) are remarkably effective against B-cell malignancies in clinical trials. However, major concerns remain regarding toxicities, such as hypogammaglobulinemia, due to B-cell aplasia or severe cytokine release syndrome after overactivation of CAR T cells. To resolve these adverse events, we aimed to develop an inducible CAR system by using a tetracycline regulation system that would be activated only in the presence of doxycycline (Dox)...
August 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27226436/generation-of-clinical-grade-cd19-specific-car-modified-cd8-memory-stem-cells-for-the-treatment-of-human-b-cell-malignancies
#15
Marianna Sabatino, Jinhui Hu, Michele Sommariva, Sanjivan Gautam, Vicki Fellowes, James D Hocker, Sean Dougherty, Haiying Qin, Christopher A Klebanoff, Terry J Fry, Ronald E Gress, James N Kochenderfer, David F Stroncek, Yun Ji, Luca Gattinoni
Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T-cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naive precursors. CD8(+)CD62L(+)CD45RA(+) naive T cells enriched by streptamer-based serial-positive selection were activated by CD3/CD28 engagement in the presence of interleukin-7 (IL-7), IL-21, and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR)...
July 28, 2016: Blood
https://www.readbyqxmd.com/read/27226366/hiv-1-specific-chimeric-antigen-receptors-based-on-broadly-neutralizing-antibodies
#16
Ayub Ali, Scott G Kitchen, Irvin S Y Chen, Hwee L Ng, Jerome A Zack, Otto O Yang
UNLABELLED: Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy...
August 1, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27163741/redirecting-t-cell-specificity-to-egfr-using-mrna-to-self-limit-expression-of-chimeric-antigen-receptor
#17
Hillary G Caruso, Hiroki Torikai, Ling Zhang, Sourindra Maiti, Jianliang Dai, Kim-Anh Do, Harjeet Singh, Helen Huls, Dean A Lee, Richard E Champlin, Amy B Heimberger, Laurence J N Cooper
Potential for on-target, but off-tissue toxicity limits therapeutic application of genetically modified T cells constitutively expressing chimeric antigen receptors (CARs) from tumor-associated antigens expressed in normal tissue, such as epidermal growth factor receptor (EGFR). Curtailing expression of CAR through modification of T cells by in vitro-transcribed mRNA species is one strategy to mitigate such toxicity. We evaluated expression of an EGFR-specific CAR coded from introduced mRNA in human T cells numerically expanded ex vivo to clinically significant numbers through coculture with activating and propagating cells (AaPC) derived from K562 preloaded with anti-CD3 antibody...
June 2016: Journal of Immunotherapy
https://www.readbyqxmd.com/read/27153556/a-role-for-multiple-chimeric-antigen-receptor-expressing-leukocytes-in-antigen-specific-responses-to-cancer
#18
Carmen S M Yong, Liza B John, Christel Devaud, Miles H Prince, Ricky W Johnstone, Joseph A Trapani, Phillip K Darcy, Michael H Kershaw
While adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells can induce remission of some tumors, the role of other CAR-modified leukocytes is not well characterized. In this study, we characterize the function of leukocytes including natural killer (NK) cells, macrophages and CAR T cells from transgenic mice expressing a CAR under the control of the pan-hematopoietic promoter, vav, and determine the ability of these mice to respond to ERB expressing tumors. We demonstrate the anti-tumor functions of leukocytes, including antigen specific cytotoxicity and cytokine secretion...
June 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27118452/phase-1-studies-of-central-memory-derived-cd19-car-t-cell-therapy-following-autologous-hsct-in-patients-with-b-cell-nhl
#19
Xiuli Wang, Leslie L Popplewell, Jamie R Wagner, Araceli Naranjo, M Suzette Blanchard, Michelle R Mott, Adam P Norris, ChingLam W Wong, Ryan Z Urak, Wen-Chung Chang, Samer K Khaled, Tanya Siddiqi, Lihua E Budde, Jingying Xu, Brenda Chang, Nikita Gidwaney, Sandra H Thomas, Laurence J N Cooper, Stanley R Riddell, Christine E Brown, Michael C Jensen, Stephen J Forman
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs...
June 16, 2016: Blood
https://www.readbyqxmd.com/read/27111235/cd19-car-t-cells-of-defined-cd4-cd8-composition-in-adult-b-cell-all-patients
#20
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M Budiarto, Emily Robinson, Natalia N Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, David G Maloney
BACKGROUND: T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells. METHODS: We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy...
June 1, 2016: Journal of Clinical Investigation
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