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Adoptive T-Cell Therapy

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https://www.readbyqxmd.com/read/28110394/chimeric-antigen-receptor-car-t-cells-lessons-learned-from-targeting-of-cd19-in-b-cell-malignancies
#1
Kevin A Hay, Cameron J Turtle
Adoptive immunotherapy with chimeric antigen receptor-modified (CAR)-T cells is a rapidly growing therapeutic approach to treating patients with refractory cancer, with over 100 clinical trials in various malignancies in progress. The enthusiasm for CAR-T cells has been driven by the clinical success of CD19-targeted CAR-T cell therapy in B-cell acute lymphoblastic leukemia, and the promising data in B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Despite the success of targeting CD19 with CAR-T cells in early clinical studies, many challenges remain to improve outcomes, reduce toxicity, and determine the appropriate settings for CAR-T cell immunotherapy...
January 21, 2017: Drugs
https://www.readbyqxmd.com/read/28110075/tlr9-mediated-regulatory-b10-cell-amplification-following-sub-total-body-irradiation-implications-in-attenuating-eae
#2
Jinsheng Hong, Jie Fang, Ruilong Lan, Qi Tan, Yeping Tian, Mei Zhang, Paul Okunieff, Lurong Zhang, Jianhua Lin, Deping Han
Autoimmunity and inflammation are controlled in part by regulatory B (Breg) cells, including the recently identified IL-10-competent B10 cell subset that represents 1%-3% of mouse spleen B cells. In this study, the influence of irradiation on Breg/B10 cell generation and IL-10 production mediated by TLR9 signaling pathways was investigated. Spleen and peritoneal cavity Breg/B10 cell frequencies were significantly expanded three weeks after sub-total body irradiation (sub-TBI, 5Gy or 10Gy) in adult male wild type (WT) C57BL/6(B6) mice but not in TLR9(-/-) mice...
January 18, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28108950/t-cell-receptor-engineered-t-cells-for-cancer-treatment-current-status-and-future-directions
#3
REVIEW
Yu Ping, Chaojun Liu, Yi Zhang
T-cell receptor (TCR)-engineered T cells are a novel option for adoptive cell therapy used for the treatment of several advanced forms of cancer. Work using TCR-engineered T cells began more than two decades ago, with numerous preclinical studies showing that such cells could mediate tumor lysis and eradication. The success of these trials provided the foundation for clinical trials, including recent clinical successes using TCR-engineered T cells to target New York esophageal squamous cell carcinoma (NY-ESO-1)...
January 20, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28099196/use-of-engineered-exosomes-expressing-hla-and-costimulatory-molecules-to-generate-antigen-specific-cd8-t-cells-for-adoptive-cell-therapy
#4
Sueon Kim, Hyun-Jung Sohn, Hyun-Joo Lee, Dae-Hee Sohn, Seung-Joo Hyun, Hyun-Il Cho, Tai-Gyu Kim
Dendritic cell-derived exosomes (DEX) comprise an efficient stimulator of T cells. However, the production of sufficient DEX remains a barrier to their broad applicability in immunotherapeutic approaches. In previous studies, genetically engineered K562 have been used to generate artificial antigen presenting cells (AAPC). Here, we isolated exosomes from K562 cells (referred to as CoEX-A2s) engineered to express human leukocyte antigen (HLA)-A2 and costimulatory molecules such as CD80, CD83, and 41BBL. CoEX-A2s were capable of stimulating antigen-specific CD8 T cells both directly and indirectly via CoEX-A2 cross-dressed cells...
January 17, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28098061/prostate-cancer-immunotherapy-particularly-in-combination-with-androgen-deprivation-or-radiation-treatment-customized-pharmacogenomic-approaches-to-overcome-immunotherapy-cancer-resistance
#5
REVIEW
C Alberti
Conventional therapeutic approaches for advanced prostate cancer - such as androgen deprivation, chemotherapy, radiation - come up often against lack of effectiveness because of possible arising of correlative cancer cell resistance and/or inadequate anti-tumor immune conditions. Whence the timeliness of resorting to immune-based treatment strategies including either therapeutic vaccination-based active immunotherapy or anti-tumor monoclonal antibody-mediated passive immunotherapy. Particularly attractive, as for research studies and clinical applications, results to be the cytotoxic T-lymphocyte check point blockade by the use of anti-CTLA-4 and PD-1 monoclonal antibodies, particularly when combined with androgen deprivation therapy or radiation...
September 2017: Il Giornale di Chirurgia
https://www.readbyqxmd.com/read/28096186/translation-reprogramming-is-an-evolutionarily-conserved-driver-of-phenotypic-plasticity-and-therapeutic-resistance-in-melanoma
#6
Paola Falletta, Luis Sanchez-Del-Campo, Jagat Chauhan, Maike Effern, Amy Kenyon, Christopher J Kershaw, Robert Siddaway, Richard Lisle, Rasmus Freter, Matthew J Daniels, Xin Lu, Thomas Tüting, Mark Middleton, Francesca M Buffa, Anne E Willis, Graham Pavitt, Ze'ev A Ronai, Tatjana Sauka-Spengler, Michael Hölzel, Colin R Goding
The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood...
January 17, 2017: Genes & Development
https://www.readbyqxmd.com/read/28093487/a-pilot-trial-of-the-combination-of-vemurafenib-with-adoptive-cell-therapy-in-patients-with-metastatic-melanoma
#7
Drew C Deniger, Mei Li M Kwong, Anna Pasetto, Mark E Dudley, John R Wunderlich, Michelle M Langhan, Chyi-Chia Richard Lee, Steven A Rosenberg
PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF(V600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration...
January 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28090089/transfer-of-minimally-manipulated-cmv-specific-t-cells-from-stem-cell-or-third-party-donors-to-treat-cmv-infection-after-allohsct
#8
M Neuenhahn, J Albrecht, M Odendahl, F Schlott, G Dössinger, M Schiemann, S Lakshmipathi, K Martin, D Bunjes, S Harsdorf, E M Weissinger, H Menzel, M Verbeek, L Uharek, N Kröger, E Wagner, G Kobbe, T Schroeder, M Schmitt, G Held, W Herr, L Germeroth, H Bonig, T Tonn, H Einsele, D H Busch, G U Grigoleit
Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo MHC-Streptamer-isolated CMV epitope-specific donor T cells...
January 16, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28076637/a-five-year-review-of-vertical-hiv-transmission-in-a-specialized-service-cross-sectional-study
#9
Izabel Cristina Hoffmann, Wendel Mombaque Dos Santos, Stela Maris de Mello Padoin, Sonia Maria Oliveira de Barros
CONTEXT AND OBJECTIVE: Healthcare professionals need to instill the process of prevention, control and treatment of people infected with HIV into care practice. Through maintaining preventive treatment among HIV-infected pregnant women, it has been demonstrated that prophylactic antiretroviral therapy, scheduled cesarean section and the prohibition of breastfeeding significantly reduce vertical HIV transmission. This study aimed to assess the rates of vertical HIV transmission in a specialized service and identify the factors associated with it...
November 2016: São Paulo Medical Journal, Revista Paulista de Medicina
https://www.readbyqxmd.com/read/28075428/balanced-secretion-of-anti-cea-x-anti-cd3-diabody-chains-using-the-2a-self-cleaving-peptide-maximizes-diabody-assembly-and-tumor-specific-cytotoxicity
#10
K Mølgaard, M Compte, N Nuñez-Prado, S L Harwood, L Sanz, L Alvarez-Vallina
Adoptive transfer of genetically engineered human cells secreting bispecific T cell engagers has shown encouraging therapeutic effects in preclinical models of cancer. However, reducing the toxicity and improving the effectiveness of this emerging immunotherapeutic strategy will be critical to its successful application. We have demonstrated that for gene-based bispecific antibody strategies, two-chain diabodies have a better safety profile than single-chain tandem scFvs, because their reduced tendency to form aggregates reduces the risk of inducing antigen-independent T cell activation...
January 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28073960/ligand-characterization-of-cyp4b1-isoforms-modified-for-high-level-expression-in-escherichia-coli-and-hepg2-cells
#11
Katharina Roellecke, Vera D Jäger, Veselin H Gyurov, John P Kowalski, Stephanie Mielke, Allan E Rettie, Helmut Hanenberg, Constanze Wiek, Marco Girhard
Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies...
January 10, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28067900/donor-cd19-car-t-cells-exert-potent-graft-versus-lymphoma-activity-with-diminished-graft-versus-host-activity
#12
Arnab Ghosh, Melody Smith, Scott E James, Marco L Davila, Enrico Velardi, Kimon V Argyropoulos, Gertrude Gunset, Fabiana Perna, Fabiana M Kreines, Emily R Levy, Sophie Lieberman, Hillary V Jay, Andrea Z Tuckett, Johannes L Zakrzewski, Lisa Tan, Lauren F Young, Kate Takvorian, Jarrod A Dudakov, Robert R Jenq, Alan M Hanash, Ana Carolina F Motta, George F Murphy, Chen Liu, Andrea Schietinger, Michel Sadelain, Marcel R M van den Brink
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies...
January 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28062570/moving-biomarkers-toward-clinical-implementation-in-kidney-transplantation
#13
Madhav C Menon, Barbara Murphy, Peter S Heeger
Long-term kidney transplant outcomes remain suboptimal, delineating an unmet medical need. Although current immunosuppressive therapy in kidney transplant recipients is effective, dosing is conventionally adjusted empirically on the basis of time after transplant or altered in response to detection of kidney dysfunction, histologic evidence of allograft damage, or infection. Such strategies tend to detect allograft rejection after significant injury has already occurred, fail to detect chronic subclinical inflammation that can negatively affect graft survival, and ignore specific risks and immune mechanisms that differentially contribute to allograft damage among transplant recipients...
January 6, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28060797/t-memory-stem-cells-in-health-and-disease
#14
REVIEW
Luca Gattinoni, Daniel E Speiser, Mathias Lichterfeld, Chiara Bonini
T memory stem (TSCM) cells are a rare subset of memory lymphocytes endowed with the stem cell-like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that TSCM cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that TSCM cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes...
January 6, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28049555/foxp3-positive-regulatory-t-cells-and-kidney-allograft%C3%A2-tolerance
#15
REVIEW
Alessandro Alessandrini, Laurence A Turka
Normal immune homeostasis is achieved by several mechanisms, and prominent among them is immunoregulation. Although several types of regulatory lymphocyte populations have been described, CD4 T cells expressing the FOXP3 transcription factor (FOXP3-positive regulatory T cells [FOXP3(+) Tregs]) are the best understood. This population of cells is critical for maintaining self-tolerance throughout the life of the organism. FOXP3(+) Tregs can develop within the thymus, but also under select circumstances, naive peripheral T cells can be induced to express FOXP3 and become stable Tregs as well...
December 31, 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/28049484/a-new-insight-in-chimeric-antigen-receptor-engineered-t-cells-for-cancer-immunotherapy
#16
REVIEW
Erhao Zhang, Hanmei Xu
Adoptive cell therapy using chimeric antigen receptor (CAR)-engineered T cells has emerged as a very promising approach to combating cancer. Despite its ability to eliminate tumors shown in some clinical trials, CAR-T cell therapy involves some significant safety challenges, such as cytokine release syndrome (CRS) and "on-target, off-tumor" toxicity, which is related to poor control of the dose, location, and timing of T cell activity. In the past few years, some strategies to avoid the side effects of CAR-T cell therapy have been reported, including suicide gene, inhibitory CAR, dual-antigen receptor, and the use of exogenous molecules as switches to control the CAR-T cell functions...
January 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28048878/th-cd-209-08-quantification-of-the-interplay-effect-in-proton-pencil-beam-scanning-treatment-of-lung
#17
M Kang, S Huang, T Solberg, R Mayer, A Thomas, B Teo, J McDonough, C Simone, L Lin
PURPOSE: To quantify the dose degradation caused by the interplay effect based on a beam specific motion analysis in proton pencil beam scanning (PBS) treatment of lung tumors METHODS: PBS plans were optimized on average CT using a beam-specific PTV method for 10 consecutive patients with locally advanced non-small-cell-lung-cancer (NSCLC) treated with proton therapy to 6660/180 cGy. End inhalation (CT0) and end exhalation (CT50) were selected as the two extreme scenarios to acquire the relative stopping power ratio difference (Δrsp) for a respiration cycle...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28047764/su-f-t-683-cancer-stem-cell-hypothesis-and-radiation-treatments
#18
E Fourkal
PURPOSE: The tumor control probability in radiation therapy allows comparing different radiation treatments to each other by means of calculating the probability that a prescribed dose of radiation eradicates or controls the tumor. In the conventional approach, all cancer cells can divide unlimited number of times and the tumor control often means eradicating every malignant cell by the radiation. In recent years however, there is a mounting consensus that in a given tumor volume there is a sub-population of cells, known as cancer stem cells (CSCs) that are responsible for tumor initiation and growth...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28028943/the-effects-of-anti-cd3-cd28-coated-beads-and-il-2-on-expanded-t-cell-for-immunotherapy
#19
Sirimarn Martkamchan, Nattawat Onlamoon, Siyu Wang, Kovit Pattanapanyasat, Palanee Ammaranond
BACKGROUND: The activation of peripheral blood mononucleated cells (PBMCs) with anti-CD3/CD28-coated magnetic beads promotes intrinsic resistance to HIV as well as cell expansion. OBJECTIVES: The aim of this study was to define an optimal cell isolation protocol for the expansion of PBMCs using anti-CD3/CD28-coated bead stimulation, with the ultimate goal of using these cells for adoptive therapy. MATERIAL AND METHODS: PBMCs were isolated from healthy donor blood samples...
September 2016: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/28027623/expression-of-a-chimeric-antigen-receptor-specific-for-donor-hla-class-i-enhances-the-potency-of-human-regulatory-t-cells-in-preventing-human-skin-transplant-rejection
#20
Dominic A Boardman, Christina Philippeos, Gilbert O Fruhwirth, Mohammad A A Ibrahim, Rosalind F Hannen, Dianne Cooper, Federica M Marelli-Berg, Fiona M Watt, Robert I Lechler, John Maher, Lesley A Smyth, Giovanna Lombardi
Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically-translatable synthetic fusion proteins which can redirect the specificity of T cells towards designated antigens...
December 27, 2016: American Journal of Transplantation
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