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 HöpkenArmin Rehm, Bahram Valamehr, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number7341
JournalNature communications
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by NIH R01 HL155150 (F.C.), NIH P01 CA111412 (J.S.M.), and research funds provided by Fate Therapeutics.

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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