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.
Highlights
Acute and chronic B-cell leukaemias can escape killing by natural killer (NK) cells
The continuously growing human NK cell line NK-92 is broadly cytotoxic against a spectrum of malignant cells [37,38,39]
NK-92 cells have been administered to over 40 patients with advanced cancers as part of phase I trials. These studies have proven the safety of repeated NK-92 infusions with no significant adverse events seen in patients
Summary
Acute and chronic B-cell leukaemias can escape killing by natural killer (NK) cells. Several pathways have recently been described for resistance such as the lack of adhesion molecules on leukaemia cells [1], expression of HLA-G [2] or the production of molecules by lymphoblasts such as MICA and MICB that bind to NK cell activating receptors like NKG2D [3,4,5]. Many leukaemic cells do not necessarily lose their ‘self’ MHC expression profile, a requirement for NK cells to overcome inhibitory signals through their killer cell immunoglobulin-like receptors [6, 7]. The introduction of chimeric antigen receptors (CAR) into cytotoxic T- or NK cells can overcome any inhibitory signal and some sig-.
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