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Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma

Oelsner, Sarah, Friede, Miriam E., Zhang, Congcong, Wagner, Juliane, Badura, Susanne, Bader, Peter, Ullrich, Evelyn, Ottmann, Oliver, Klingemann, Hans, Tonn, Torsten and Wels, Winfried S. 2017. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytotherapy 19 (2) , pp. 235-249. 10.1016/j.jcyt.2016.10.009

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Abstract

Background aims Natural killer (NK) cells can rapidly respond to transformed and stressed cells and represent an important effector cell type for adoptive immunotherapy. In addition to donor-derived primary NK cells, continuously expanding cytotoxic cell lines such as NK-92 are being developed for clinical applications. Methods To enhance their therapeutic utility for the treatment of B-cell malignancies, we engineered NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors (CARs) that target CD19 and contain human CD3ζ (CAR 63.z), composite CD28-CD3ζ or CD137-CD3ζ signaling domains (CARs 63.28.z and 63.137.z). Results Exposure of CD19-positive targets to CAR NK-92 cells resulted in formation of conjugates between NK and cancer cells, NK-cell degranulation and selective cytotoxicity toward established B-cell leukemia and lymphoma cells. Likewise, the CAR NK cells displayed targeted cell killing of primary pre-B-ALL blasts that were resistant to parental NK-92. Although all three CAR NK-92 cell variants were functionally active, NK-92/63.137.z cells were less effective than NK-92/63.z and NK-92/63.28.z in cell killing and cytokine production, pointing to differential effects of the costimulatory CD28 and CD137 domains. In a Raji B-cell lymphoma model in NOD-SCID IL2R γnull mice, treatment with NK-92/63.z cells, but not parental NK-92 cells, inhibited disease progression, indicating that selective cytotoxicity was retained in vivo. Conclusions Our data demonstrate that it is feasible to generate CAR-engineered NK-92 cells with potent and selective antitumor activity. These cells may become clinically useful as a continuously expandable off-the-shelf cell therapeutic agent.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: adoptive immunotherapy; B-cell malignancies; CD19; chimeric antigen receptor; natural killer cells
Publisher: Elsevier
ISSN: 1465-3249
Date of First Compliant Deposit: 9 December 2016
Date of Acceptance: 24 October 2016
Last Modified: 24 Apr 2018 17:52
URI: http://orca-mwe.cf.ac.uk/id/eprint/96745

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