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J Cell Mol Med. 2016 Jul;20(7):1287-94. doi: 10.1111/jcmm.12810. Epub 2016 Mar 23.

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

Author information

1
Department of Hematology, J.W. Goethe University Frankfurt/Main, Frankfurt, Germany.
2
Institute for Transfusion Medicine and Immunohematology, J.W. Goethe University Frankfurt/Main, Red Cross Blood Donor Service Baden-Württemberg-Hessen, Dresden, Germany.
3
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.
4
Nantkwest Inc & Tufts University Medical School, Boston, MA, USA.
5
Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North/East, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany.

Abstract

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.

KEYWORDS:

CAR; NK-92; cellular immunotherapy; leukaemia; natural killer cell; αCD19

PMID:
27008316
PMCID:
PMC4929308
DOI:
10.1111/jcmm.12810
[Indexed for MEDLINE]
Free PMC Article

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