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 ORCID: https://orcid.org/0000-0001-9559-1330, 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:	02 Dec 2024 21:45
URI:	https://orca.cardiff.ac.uk/id/eprint/96745

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