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

Cichocki, F.; Bjordahl, R.; Goodridge, J.P.; Mahmood, S.; Gaidarova, S.; Abujarour, R.; Davis, Z.B.; Merino, A.; Tuininga, K.; Wang, H.; Kumar, A.; Groff, B.; Witty, A.; Bonello, G.; Huffman, J.; Dailey, T.; Lee, T.T.; Malmberg, K.J.; Walcheck, B.; Höpken, U.; Rehm, A.; Valamehr, B.; Miller, J.S.

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

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Item Type:	Article
Title:	Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma
Creators Name:	Cichocki, F., Bjordahl, R., Goodridge, J.P., Mahmood, S., Gaidarova, S., Abujarour, R., Davis, Z.B., Merino, A., Tuininga, K., Wang, H., Kumar, A., Groff, B., Witty, A., Bonello, G., Huffman, J., Dailey, T., Lee, T.T., Malmberg, K.J., Walcheck, B., Höpken, U., Rehm, A., Valamehr, B. and Miller, J.S.
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.
Keywords:	B-Cell Maturation Antigen, Multiple Myeloma, NK Cell Lectin-Like Receptor Subfamily D, Natural Killer Cell Receptors, Natural Killer Cells
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	13
Number:	1
Page Range:	7341
Date:	29 November 2022
Official Publication:	https://doi.org/10.1038/s41467-022-35127-2
PubMed:	View item in PubMed

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