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CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies

Romanski, Annette, Uherek, Christoph, Bug, Gesine, Seifried, Erhard, Klingemann, Hans, Wels, Winfried S., Ottmann, Oliver and Tonn, Torsten 2016. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Journal of Cellular and Molecular Medicine 20 (7) , pp. 1287-1294. 10.1111/jcmm.12810

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Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The ‘first generation’ CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Uncontrolled Keywords: natural killer cell; NK-92; CAR ; αCD19; cellular immunotherapy; leukaemia
Publisher: Wiley
ISSN: 1582-1838
Date of Acceptance: 4 December 2015
Last Modified: 03 Sep 2019 08:16

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