Open AccessCD 19‐ CAR engineered NK ‐92 cells are sufficient to overcome NK cell resistance in B‐cell malignancies
Author(s) -
Romanski Annette,
Uherek Christoph,
Bug Gesine,
Seifried Erhard,
Klingemann Hans,
Wels Winfried S.,
Ottmann Oliver G.,
Tonn Torsten
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12810
Subject(s) - cytotoxic t cell , lymphoblast , interleukin 21 , chimeric antigen receptor , cytolysis , cell culture , nk 92 , cytotoxicity , antigen , cancer research , biology , immunology , t cell , immune system , in vitro , cd8 , genetics , biochemistry
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‐ CD 19‐ CAR (α CD 19‐ CAR ) engineered NK ‐92 cells can regain significant cytotoxicity against CD 19 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 ( CD 19) antibody fragment, coupled to a flexible hinge region, the CD 3ζ chain and a Myc‐tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK ‐92 and transduced α CD 19‐ CAR NK ‐92 cells towards CD 19 negative targets was found. However, α CD 19‐ CAR NK ‐92 cells specifically and efficiently lysed CD 19 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.