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Cytotherapy. 2017 Feb;19(2):235-249. doi: 10.1016/j.jcyt.2016.10.009. Epub 2016 Nov 22.

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

Author information

1
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.
2
Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, Goethe University Frankfurt, Frankfurt, Germany; LOEWE Center for Cell and Gene Therapy, Goethe University Frankfurt, Frankfurt, Germany.
3
Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany.
4
Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, Goethe University Frankfurt, Frankfurt, Germany.
5
Department of Haematology, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.
6
NantKwest, Inc., Culver City, California, USA.
7
Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, Dresden and Transfusion Medicine, Medical Faculty Carl Gustav Carus, TU Dresden, Germany.
8
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, Germany. Electronic address: wels@gsh.uni-frankfurt.de.

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.

KEYWORDS:

B-cell malignancies; CD19; adoptive immunotherapy; chimeric antigen receptor; natural killer cells

PMID:
27887866
DOI:
10.1016/j.jcyt.2016.10.009
[Indexed for MEDLINE]

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