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      Toward the development of true “off‐the‐shelf” synthetic T‐cell immunotherapy

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          Abstract

          Recent outstanding clinical results produced by engineered T cells, including chimeric antigen receptors, have already facilitated further research that broadens their applicability. One such direction is to explore new T cell sources for allogeneic “off‐the‐shelf” adoptive immunotherapy. Human pluripotent stem cells could serve as an alternative cell source for this purpose due to their unique features of infinite propagation ability and pluripotency. Here, we describe the current state of engineered T cell transfer with the focus on cell manufacturing processes and the potentials and challenges of induced pluripotent stem cell‐derived T cells as a starting material to construct off‐the‐shelf T‐cell banks.

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          Most cited references28

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          IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor

          Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 × 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 × 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 × 19 CAR-T cell therapy. Depletion of recipient T cells before 7 × 19 CAR-T cell administration dampened the therapeutic effects of 7 × 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti-tumor activity. Following treatment of mice with 7 × 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors.
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            HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells

            Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this ‘missing self’ response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies, and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.
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              Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy.

              Progress in adoptive T-cell therapy for cancer and infectious diseases is hampered by the lack of readily available, antigen-specific, human T lymphocytes. Pluripotent stem cells could provide an unlimited source of T lymphocytes, but the therapeutic potential of human pluripotent stem cell-derived lymphoid cells generated to date remains uncertain. Here we combine induced pluripotent stem cell (iPSC) and chimeric antigen receptor (CAR) technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture. These iPSC-derived, CAR-expressing T cells display a phenotype resembling that of innate γδ T cells. Similar to CAR-transduced, peripheral blood γδ T cells, the iPSC-derived T cells potently inhibit tumor growth in a xenograft model. This approach of generating therapeutic human T cells 'in the dish' may be useful for cancer immunotherapy and other medical applications.
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                Author and article information

                Contributors
                kaneko.shin@cira.kyoto-u.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                01 January 2019
                January 2019
                : 110
                : 1 ( doiID: 10.1111/cas.2019.110.issue-1 )
                : 16-22
                Affiliations
                [ 1 ] Center for iPS Research and Application (CiRA) Kyoto University Kyoto Japan
                Author notes
                [*] [* ] Correspondence

                Shin Kaneko, Center for iPS Research and Application (CiRA), Kyoto University, Kyoto, Japan.

                Email: kaneko.shin@ 123456cira.kyoto-u.ac.jp

                Article
                CAS13892
                10.1111/cas.13892
                6317915
                30485606
                46adecb5-8b3f-4c02-9df5-fe20c304a114
                © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 01 September 2018
                : 19 November 2018
                : 22 November 2018
                Page count
                Figures: 4, Tables: 0, Pages: 8, Words: 5147
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                cas13892
                January 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.4 mode:remove_FC converted:03.01.2019

                Oncology & Radiotherapy
                antigen specificity,ips cell,regenerative immunotherapy,t cell differentiation,t cell rejuvenation

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