Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 11 2022
29 11 2022
Historique:
received:
23
02
2022
accepted:
20
11
2022
entrez:
29
11
2022
pubmed:
30
11
2022
medline:
2
12
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36446823
doi: 10.1038/s41467-022-35127-2
pii: 10.1038/s41467-022-35127-2
pmc: PMC9709157
doi:
Substances chimiques
B-Cell Maturation Antigen
0
Receptors, Natural Killer Cell
0
NK Cell Lectin-Like Receptor Subfamily D
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
7341Subventions
Organisme : NCI NIH HHS
ID : P01 CA111412
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA203348
Pays : United States
Informations de copyright
© 2022. The Author(s).
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