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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: |
Cichocki, F.  ORCID: https://orcid.org/0000-0003-3043-0653, Bjordahl, R., Goodridge, J.P., Mahmood, S., Gaidarova, S., Abujarour, R., Davis, Z.B., Merino, A. ORCID: https://orcid.org/0000-0003-4433-0127, Tuininga, K., Wang, H., Kumar, A., Groff, B., Witty, A., Bonello, G., Huffman, J., Dailey, T., Lee, T.T., Malmberg, K.J. ORCID: https://orcid.org/0000-0002-8718-9373, Walcheck, B., Höpken, U. ORCID: https://orcid.org/0000-0002-0776-4893, Rehm, A. ORCID: https://orcid.org/0000-0001-7490-1950, Valamehr, B. ORCID: https://orcid.org/0000-0002-5917-3585 and Miller, J.S. ORCID: https://orcid.org/0000-0002-0339-4944
|
| 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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