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      Induced Pluripotent Stem Cell (iPSC)–Derived Lymphocytes for Adoptive Cell Immunotherapy: Recent Advances and Challenges

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          Abstract

          Purpose of Review

          In the rapidly developing field of adoptive cell immunotherapy, there is urgent need for discoveries that would improve outcomes, extend the applicability, and reduce the costs. Induced pluripotent stem cells (iPSC) can be a source of broadly applicable cellular immunotherapeutics, which have been manufactured, validated, and banked in advance, and can be applied across HLA barriers. Here, we discuss the recent advances and challenges in the generation of iPSC-derived cellular products for cancer therapy.

          Recent Findings

          iPSCs can be differentiated to functional tumor-specific T and NK cells in vitro with demonstrable in vitro and in vivo anti-tumor activity. Genetic modifications employed at the iPSC level can deliver desirable immunotherapeutic attributes to the generated immune effectors. iPSC-NK cells are currently evaluated in a clinical setting and pre-clinical testing of iPSC-T cells shows promising results but their production seems more challenging.

          Summary

          The use of iPSCs for the generation of tumor-targeting T/NK cells constitutes a feasible strategy to overcome limitations in manufacturing, efficacy, and applicability of cellular therapeutics.

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          Most cited references39

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          NK cells and cancer: you can teach innate cells new tricks.

          Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer.
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            Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity

            Chimeric antigen receptors (CARs) significantly enhance anti-tumor activity of immune effector cells. While most studies have evaluated CAR-expression in T cells, here we evaluate different CAR constructs that improve natural killer (NK) cell-mediated killing. We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling. NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared to T-CAR expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR expressing cells. Using an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared to PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. Additionally, NK-CAR-iPSC-NK cells demonstrate similar in vivo activity as T-CAR-expressing T cells, though with less toxicity. These NK-CAR-iPSC-NK cells now provide standardized, targeted “off the shelf” lymphocytes for anti-cancer immunotherapy. Natural killer (NK) cells are a key part of the immune system’s ability to mediate anti-cancer activity. Kaufman and colleagues utilize human iPSCs to produce NK cells with novel chimeric antigen receptors that specifically target cancer cells in an antigen-specific manner to improve survival in an ovarian cancer xenograft model.
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              Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia

              Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.
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                Author and article information

                Contributors
                a.nianias@amsterdamumc.nl
                +31 (0) 204447413 , m.themeli@amsterdamumc.nl
                Journal
                Curr Hematol Malig Rep
                Curr Hematol Malig Rep
                Current Hematologic Malignancy Reports
                Springer US (New York )
                1558-8211
                1558-822X
                26 June 2019
                26 June 2019
                2019
                : 14
                : 4
                : 261-268
                Affiliations
                ISNI 0000000084992262, GRID grid.7177.6, Department of Hematology, , Amsterdam University Medical Centers, Cancer Center Amsterdam, ; Location VUmc, Amsterdam, Netherlands
                Article
                528
                10.1007/s11899-019-00528-6
                6647376
                31243643
                f60fafb8-b722-4ced-9c2c-333e78653b41
                © The Author(s) 2019

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: Amsterdam UMC (VU University Amsterdam)
                Categories
                CART and Immunotherapy (M Ruella and P Hanley, Section Editors)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Hematology
                induced pluripotent stem cells,adoptive cell immunotherapy,nk cells,t cells,off-the-shelf

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