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

  • Nat Commun. 2022 Nov 29;13(1):7341. doi: 10.1038/s41467-022-35127-2.
Frank Cichocki  #  1 ,  Ryan Bjordahl  #  2 ,  Jodie P Goodridge  2 ,  Sajid Mahmood  2 ,  Svetlana Gaidarova  2 ,  Ramzey Abujarour  2 ,  Zachary B Davis  1 ,  Aimee Merino  1 ,  Katie Tuininga  1 ,  Hongbo Wang  1 ,  Akhilesh Kumar  1 ,  Brian Groff  2 ,  Alec Witty  2 ,  Greg Bonello  2 ,  Janel Huffman  2 ,  Thomas Dailey  2 ,  Tom T Lee  2 ,  Karl-Johan Malmberg  3 ,  Bruce Walcheck  4 ,  Uta Höpken  5 ,  Armin Rehm  5 ,  Bahram Valamehr  6 ,  Jeffrey S Miller  7
Affiliations
  • 1. University of Minnesota, Department of Medicine, Minneapolis, MN, 55455, USA.
  • 2. Fate Therapeutics, San Diego, CA, 92121, USA.
  • 3. Oslo University Hospital, Oslo, Norway.
  • 4. University of Minnesota, Department of Veterinary and Biomedical Sciences, St. Paul, MN, 55108, USA.
  • 5. Max-Delbrück-Center for Molecular Medicine, MDC, Berlin, Germany.
  • 6. Fate Therapeutics, San Diego, CA, 92121, USA. [email protected].
  • 7. University of Minnesota, Department of Medicine, Minneapolis, MN, 55455, USA. [email protected].
  • # Contributed equally.
PMID: 36446823 DOI: 10.1038/s41467-022-35127-2
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.

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