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https://www.readbyqxmd.com/read/29023549/supraphysiologic-control-over-hiv-1-replication-mediated-by-cd8-t-cells-expressing-a-re-engineered-cd4-based-chimeric-antigen-receptor
#1
Rachel S Leibman, Max W Richardson, Christoph T Ellebrecht, Colby R Maldini, Joshua A Glover, Anthony J Secreto, Irina Kulikovskaya, Simon F Lacey, Sarah R Akkina, Yanjie Yi, Farida Shaheen, Jianbin Wang, Keith A Dufendach, Michael C Holmes, Ronald G Collman, Aimee S Payne, James L Riley
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs...
October 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28924019/kinetics-and-biomarkers-of-severe-cytokine-release-syndrome-after-cd19-chimeric-antigen-receptor-modified-t-cell-therapy
#2
Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Juliane Gust, W Conrad Liles, Mark M Wurfel, José A López, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified T cells (CAR-T) has produced impressive antitumor responses in patients with refractory CD19(+) B cell malignancies, but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR-T cells...
September 18, 2017: Blood
https://www.readbyqxmd.com/read/28818060/rna-transfection-of-%C3%AE-%C3%AE-t-cells-with-a-chimeric-antigen-receptor-or-an-%C3%AE-%C3%AE-t-cell-receptor-a-safer-alternative-to-genetically-engineered-%C3%AE-%C3%AE-t-cells-for-the-immunotherapy-of-melanoma
#3
Dennis C Harrer, Bianca Simon, Shin-Ichiro Fujii, Kanako Shimizu, Ugur Uslu, Gerold Schuler, Kerstin F Gerer, Stefanie Hoyer, Jan Dörrie, Niels Schaft
BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA...
August 17, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28708810/role-of-normalized-t-cell-subsets-in-predicting-comorbidities-in-a-large-cohort-of-geriatric-hiv-infected-patients
#4
Andrea Calcagno, Stefania Piconi, Emanuele Focà, Silvia Nozza, Federica Carli, Chiara Montrucchio, Annamaria M Cattelan, Giancarlo Orofino, Benedetto M Celesia, Valentina Morena, Giuseppe V De Socio, Giovanni Guaraldi
BACKGROUND: Adults aging with HIV are at greater risk for several comorbidities. The CD4 cell count and CD4/CD8 ratio often fail to normalize in elderly patients despite prolonged antiretroviral therapy; this has been associated with concomitant diseases and poor prognosis. METHODS: A cross-sectional analysis in antiretroviral-treated HIV-positive patients aged 65 years and older. The aim of the study was to describe the predictors of normalized T-cell subsets ("nT", CD4/CD8 ratio ≥1 and CD4 ≥500 cells/μL) in a cohort of geriatric HIV-positive patients and its association with HIV-associated non-AIDS conditions (HANA)...
November 1, 2017: Journal of Acquired Immune Deficiency Syndromes: JAIDS
https://www.readbyqxmd.com/read/28697888/regulated-expansion-and-survival-of-chimeric-antigen-receptor-modified-t-cells-using-small-molecule-dependent-inducible-myd88-cd40
#5
Aaron E Foster, Aruna Mahendravada, Nicholas P Shinners, Wei-Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L Shaw, Sunandan Saha, MyLinh T Duong, Matthew R Collinson-Pautz, David L Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J Henri Bayle, Kevin M Slawin, David M Spencer
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4(+) and CD8(+) T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28659311/memory-t-cells-expressing-an-nkg2d-car-efficiently-target-osteosarcoma-cells
#6
Lucía Fernández, Jean-Yves Metais, Adela Escudero, María Vela, Jaime Valentín, Isabel Vallcorba, Alejandra Leivas, Juan Torres, Antonio Valeri, Ana Patiño-García, Joaquín Martínez, Wing Leung, Antonio Pérez-Martínez
Purpose: NKG2D ligands (NKG2DL) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. Various immune cells express NKG2D receptors, including natural killer (NK) cells and CD8(+) T cells. Interactions between NKG2DL and NKG2D receptors are essential for NK-cell elimination of osteosarcoma tumor-initiating cells. In this report, we used NKG2D-NKG2DL interactions to optimize an immunotherapeutic strategy against osteosarcoma...
June 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28651374/cd70-a-novel-target-of-car-t-cell-therapy-for-gliomas
#7
Linchun Jin, Haitao Ge, Yu Long, Changlin Yang, Yifan Emily Chang, Luyan Mu, Elias J Sayour, Gabriel De Leon, Qiong J Wang, James C Yang, Paul S Kubilis, Hongbo Bao, Songsong Xia, Dunyue Lu, Yingjun Kong, Li Hu, Yujiao Shang, Chencheng Jiang, Jing Nie, Shimin Li, Yunhe Gu, Jiahang Sun, Duane A Mitchell, Zhiguo Lin, Jianping Huang
Background: Cancer immunotherapy represents a promising treatment approach for malignant-gliomas, but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified CD70 as a novel immunosuppressive ligand and glioma target. Methods: Normal tissues derived from 52 different organs, and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression...
June 23, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28546503/frontline-science-functionally-impaired-geriatric-car-t-cells-rescued-by-increased-%C3%AE-5%C3%AE-1-integrin-expression
#8
Prajna Guha, Marissa Cunetta, Ponnandai Somasundar, N Joseph Espat, Richard P Junghans, Steven C Katz
Chimeric antigen receptor expressing T cells (CAR-T) are a promising form of immunotherapy, but the influence of age-related immune changes on CAR-T production remains poorly understood. We showed that CAR-T cells from geriatric donors (gCAR-T) are functionally impaired relative to CAR-T from younger donors (yCAR-T). Higher transduction efficiencies and improved cell expansion were observed in yCAR-T cells compared with gCAR-T. yCAR-T demonstrated significantly increased levels of proliferation and signaling activation of phosphorylated (p)Erk, pAkt, pStat3, and pStat5...
August 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28472064/impact-of-illicit-opioid-use-on-t-cell-subsets-among-hiv-infected-adults
#9
E Jennifer Edelman, Kaku So-Armah, Debbie M Cheng, Margaret F Doyle, Sharon M Coleman, Carly Bridden, Natalia Gnatienko, Dmitry A Lioznov, Elena Blokhina, Matthew S Freiberg, Evgeny M Krupitsky, Brinda Emu, Jeffrey H Samet
OBJECTIVES: Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied. METHODS: To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St...
2017: PloS One
https://www.readbyqxmd.com/read/28408462/intent-to-treat-leukemia-remission-by-cd19-car-t-cells-of-defined-formulation-and-dose-in-children-and-young-adults
#10
Rebecca A Gardner, Olivia Finney, Colleen Annesley, Hannah Brakke, Corinne Summers, Kasey Leger, Marie Bleakley, Christopher Brown, Stephanie Mgebroff, Karen S Kelly-Spratt, Virginia Hoglund, Catherine Lindgren, Assaf P Oron, Daniel Li, Stanley R Riddell, Julie R Park, Michael C Jensen
Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation...
June 22, 2017: Blood
https://www.readbyqxmd.com/read/28405508/antigen-receptor-redirected-t-cells-derived-from-hematopoietic-precursor-cells-lack-expression-of-the-endogenous-tcr-cd3-receptor-and-exhibit-specific-antitumor-capacities
#11
Yasmine Van Caeneghem, Stijn De Munter, Paola Tieppo, Glenn Goetgeluk, Karin Weening, Greet Verstichel, Sarah Bonte, Tom Taghon, Georges Leclercq, Tessa Kerre, Reno Debets, David Vermijlen, Hinrich Abken, Bart Vandekerckhove
Recent clinical studies indicate that adoptive T-cell therapy and especially chimeric antigen receptor (CAR) T-cell therapy is a very potent and potentially curative treatment for B-lineage hematologic malignancies. Currently, autologous peripheral blood T cells are used for adoptive T-cell therapy. Adoptive T cells derived from healthy allogeneic donors may have several advantages; however, the expected occurrence of graft versus host disease (GvHD) as a consequence of the diverse allogeneic T-cell receptor (TCR) repertoire expressed by these cells compromises this approach...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28331616/ex-vivo-akt-inhibition-promotes-the-generation-of-potent-cd19car-t-cells-for-adoptive-immunotherapy
#12
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
#13
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
#14
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...
March 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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