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CAR NK cell production from human cord blood cells is enhanced by stimulation of the IL15 receptor on NK progenitor cells

ABSTRACT: Human cord blood (CB)-derived CAR NK cells have demonstrated significant anti-tumor efficacy in clinical trials. We recently reported that CB-derived CAR NK cells are mainly derived from CD7+CD56-CD34-HLA-DR-Lin- NK precursors. Here we show that CAR NK cell production from human CB cells can be enhanced by stimulation of the IL15 receptor on NK precursors. In CB CD56-CD34-HLADR-Lin- cells, the IL15 receptor was expressed exclusively on the CD7+ NK cell precursors but not on the CD7- population. The production of mature NK cells from the purified NK cell precursors or CD3- CB cells was significantly enhanced by using K562 feeder cells expressing membrane-bound (mb) IL15 in addition to 4-1BB ligand and mbIL21. The in vitro and in vivo anti-tumor efficacy of CAR NK cells generated using K562 feeder cells expressing 4-1BBL, mbIL15 and mbIL21 was comparable to that of CAR NK cells generated using the K562 feeder cells expressing only 4-1BBL and mbIL21. These results suggest that the use of K562 feeder cells expressing mbIL15 in addition to 4-1BBL and mbIL21 increases the yield of CAR NK cell production from CB cells, while the clinical efficacy and safety of the CAR NK cells generated should be tested in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295031 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.

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CAR NK cell production from human cord blood cells is enhanced by stimulation of the IL15 receptor on NK progenitor cells

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