Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma


  • F. Cichocki
  • R. Bjordahl
  • J.P. Goodridge
  • S. Mahmood
  • S. Gaidarova
  • R. Abujarour
  • Z.B. Davis
  • A. Merino
  • K. Tuininga
  • H. Wang
  • A. Kumar
  • B. Groff
  • A. Witty
  • G. Bonello
  • J. Huffman
  • T. Dailey
  • T.T. Lee
  • K.J. Malmberg
  • B. Walcheck
  • U. Höpken
  • A. Rehm
  • B. Valamehr
  • J.S. Miller


  • Nature Communications


  • Nat Commun 13 (1): 7341


  • Allogeneic natural killer (NK) cell adoptive transfer is a promising treatment for several cancers but is less effective for the treatment of multiple myeloma. In this study, we report on quadruple gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells designed for mass production from a renewable source and for dual targeting against multiple myeloma through the introduction of an NK cell-optimized chimeric antigen receptor (CAR) specific for B cell maturation antigen (BCMA) and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity when combined with therapeutic anti-CD38 antibodies. Additionally, these cells express a membrane-bound interleukin-15 fusion molecule to enhance function and persistence along with knock out of CD38 to prevent antibody-mediated fratricide and enhance NK cell metabolic fitness. In various preclinical models, including xenogeneic adoptive transfer models, quadruple gene-engineered NK cells consistently demonstrate durable antitumor activity independent of exogenous cytokine support. Results presented here support clinical translation of this off-the-shelf strategy for effective treatment of multiple myeloma.