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

Frank Cichocki, Ryan Bjordahl, Jodie P. Goodridge, Sajid Mahmood, Svetlana Gaidarova, Ramzey Abujarour, Zachary B. Davis, Aimee Merino, Katie Tuininga, Hongbo Wang, Akhilesh Kumar, Brian Groff, Alec Witty, Greg Bonello, Janel Huffman, Thomas Dailey, Tom T. Lee, Karl-Johan Malmberg, Bruce Walcheck, Uta Höpken, Armin Rehm, Bahram Valamehr () and Jeffrey S. Miller ()
Additional contact information
Frank Cichocki: University of Minnesota, Department of Medicine
Ryan Bjordahl: Fate Therapeutics
Jodie P. Goodridge: Fate Therapeutics
Sajid Mahmood: Fate Therapeutics
Svetlana Gaidarova: Fate Therapeutics
Ramzey Abujarour: Fate Therapeutics
Zachary B. Davis: University of Minnesota, Department of Medicine
Aimee Merino: University of Minnesota, Department of Medicine
Katie Tuininga: University of Minnesota, Department of Medicine
Hongbo Wang: University of Minnesota, Department of Medicine
Akhilesh Kumar: University of Minnesota, Department of Medicine
Brian Groff: Fate Therapeutics
Alec Witty: Fate Therapeutics
Greg Bonello: Fate Therapeutics
Janel Huffman: Fate Therapeutics
Thomas Dailey: Fate Therapeutics
Tom T. Lee: Fate Therapeutics
Karl-Johan Malmberg: Oslo University Hospital
Bruce Walcheck: University of Minnesota, Department of Veterinary and Biomedical Sciences
Uta Höpken: Max-Delbrück-Center for Molecular Medicine, MDC
Armin Rehm: Max-Delbrück-Center for Molecular Medicine, MDC
Bahram Valamehr: Fate Therapeutics
Jeffrey S. Miller: University of Minnesota, Department of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35127-2

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