Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells

Mol Oncol. 2014 Mar;8(2):297-310. doi: 10.1016/j.molonc.2013.12.001. Epub 2013 Dec 12.


Reprogramming of NK cells with a chimeric antigen receptor (CAR) proved an effective strategy to increase NK cell reactivity and recognition specificity toward tumor cells. To enhance the cytotoxicity of NK cells against CD138-positive multiple myeloma (MM) cells, we generated genetically modified NK-92MI cells carrying a CAR that consists of an anti-CD138 single-chain variable fragment (scFv) fused to the CD3ζ chain as a signaling moiety. The genetic modification through a lentiviral vector did not affect the intrinsic cytolytic activity of NK-92MI toward human erythroleukemic cell line K562 cells or CD138-negative targets. However, these retargeted NK-92MI (NK-92MI-scFv) displayed markedly enhanced cytotoxicity against CD138-positive human MM cell lines (RPMI8226, U266 and NCI-H929) and primary MM cells at various effector-to-target ratios (E:T) as compared to the empty vector-transfected NK-92MI (NK-92MI-mock). In line with the enhanced cytotoxicity of NK-92MI-scFv, significant elevations in the secretion of granzyme B, interferon-γ and proportion of CD107a expression were also found in NK-92MI-scFv in response to CD138-positive targets compared with NK-92MI-mock. Most importantly, the enhancement in the cytotoxicity of NK-92MI-scFv did not attenuate with 10Gy-irradiation that sufficiently blocked cell proliferation. Moreover, the irradiated NK-92MI-scFv exerted definitely intensified anti-tumor activity toward CD138-positive MM cells than NK-92MI-mock in the xenograft NOD-SCID mouse model. This study provides the rationale and feasibility for adoptive immunotherapy with CD138-specific CAR-modified NK cells in CD138-positive plasmacytic malignancies, which potentially further improves remission quality and prolongs the remission duration of patients with MM after upfront chemotherapy.

Keywords: Adoptive immunotherapy; CD138 (syndecan-1); Chimeric antigen receptor; Multiple myeloma; NK cells.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antibodies, Neoplasm* / genetics
  • Antibodies, Neoplasm* / immunology
  • Cell Line, Tumor
  • Female
  • Humans
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / pathology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / immunology
  • Multiple Myeloma* / pathology
  • Multiple Myeloma* / therapy
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / immunology
  • Single-Chain Antibodies* / genetics
  • Single-Chain Antibodies* / immunology
  • Syndecan-1* / genetics
  • Syndecan-1* / immunology
  • Transfection*


  • Antibodies, Neoplasm
  • Neoplasm Proteins
  • SDC1 protein, human
  • Single-Chain Antibodies
  • Syndecan-1