2. Academic Validation
  3. Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma

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

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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