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      Characterization of clinical grade CD19 chimeric antigen receptor T cells produced using automated CliniMACS Prodigy system

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          Abstract

          Background

          Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkin’s lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production.

          Method

          In this study, we describe the successful production of clinical grade CD19 CAR T cells using the Miltenyi CliniMACS Prodigy Automated Cell Processor at University of Colorado Anschutz Medical Campus in a rapid manner with a high frequent CD19 CAR expression.

          Results

          The final CAR T-cell product is highly active, low in immune suppression, and absent in exhaustion. Full panel cytokine assays also showed elevated production of Th1 cytokines upon IL-2 stimulation when specifically killing CD19+ target cells.

          Conclusion

          These results demonstrate the feasibility of producing CAR T cells locally in a university hospital setting using automated cell processor for future clinical applications.

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          Most cited references 41

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          Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells.

          Chimeric antigen receptors (CARs) redirect T cell cytotoxicity against cancer cells, providing a promising approach to cancer immunotherapy. Despite extensive clinical use, the attributes of CAR co-stimulatory domains that impact persistence and resistance to exhaustion of CAR-T cells remain largely undefined. Here, we report the influence of signaling domains of coreceptors CD28 and 4-1BB on the metabolic characteristics of human CAR T cells. Inclusion of 4-1BB in the CAR architecture promoted the outgrowth of CD8(+) central memory T cells that had significantly enhanced respiratory capacity, increased fatty acid oxidation and enhanced mitochondrial biogenesis. In contrast, CAR T cells with CD28 domains yielded effector memory cells with a genetic signature consistent with enhanced glycolysis. These results provide, at least in part, a mechanistic insight into the differential persistence of CAR-T cells expressing 4-1BB or CD28 signaling domains in clinical trials and inform the design of future CAR T cell therapies.
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            Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells.

            T-bet is a member of the T-box family of transcription factors that appears to regulate lineage commitment in CD4 T helper (TH) lymphocytes in part by activating the hallmark TH1 cytokine, interferon-gamma (IFN-gamma). IFN-gamma is also produced by natural killer (NK) cells and most prominently by CD8 cytotoxic T cells, and is vital for the control of microbial pathogens. Although T-bet is expressed in all these cell types, it is required for control of IFN-gamma production in CD4 and NK cells, but not in CD8 cells. This difference is also apparent in the function of these cell subsets. Thus, the regulation of a single cytokine, IFN-gamma, is controlled by distinct transcriptional mechanisms within the T cell lineage.
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              • Article: not found

              T-bet: a bridge between innate and adaptive immunity.

              Originally described over a decade ago as a T cell transcription factor regulating T helper 1 cell lineage commitment, T-bet is now recognized as having an important role in many cells of the adaptive and innate immune system. T-bet has a fundamental role in coordinating type 1 immune responses by controlling a network of genetic programmes that regulate the development of certain immune cells and the effector functions of others. Many of these transcriptional networks are conserved across innate and adaptive immune cells and these shared mechanisms highlight the biological functions that are regulated by T-bet.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                05 October 2018
                : 12
                : 3343-3356
                Affiliations
                [1 ]Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, enkhtsetseg.purev@ 123456ucdenver.edu
                [2 ]Division of Immunology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
                [3 ]Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
                Author notes
                Correspondence: Enkhtsetseg Purev, Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, USA, Email enkhtsetseg.purev@ 123456ucdenver.edu
                Article
                dddt-12-3343
                10.2147/DDDT.S175113
                6181073
                © 2018 Zhang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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