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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cell Lineage
  • Cytotoxicity, Immunologic
  • Genetic Engineering*
  • Humans
  • Killer Cells, Natural / immunology*
  • Lymphoma, B-Cell / immunology*
  • Lymphoma, B-Cell / pathology
  • Receptors, Antigen, T-Cell / metabolism*
  • Retroviridae / metabolism
  • Single-Chain Antibodies / metabolism
  • Tissue Donors
  • Transfection

Substances

  • CD19-specific chimeric antigen receptor
  • Receptors, Antigen, T-Cell
  • Single-Chain Antibodies