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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Gr, 2022. "Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35127-2
    DOI: 10.1038/s41467-022-35127-2
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    References listed on IDEAS

    as
    1. Mehmet Kemal Samur & Mariateresa Fulciniti & Anil Aktas Samur & Abdul Hamid Bazarbachi & Yu-Tzu Tai & Rao Prabhala & Alejandro Alonso & Adam S. Sperling & Timothy Campbell & Fabio Petrocca & Kristen H, 2021. "Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    2. Sarah A. Laurent & Franziska S. Hoffmann & Peer-Hendrik Kuhn & Qingyu Cheng & Yuanyuan Chu & Marc Schmidt-Supprian & Stefanie M. Hauck & Elisabeth Schuh & Markus Krumbholz & Heike Rübsamen & Johanna W, 2015. "γ-secretase directly sheds the survival receptor BCMA from plasma cells," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
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