piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells

Promising progress has been made in adoptive transfer of allogeneic natural killer (NK) cells to treat relapsed or refractory acute myeloid leukemia (AML). In this regard, chimeric antigen receptor (CAR)-modification of NK cells is considered as a compelling approach to augment the specificity and c...

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Bibliographic Details
Published in:Molecular therapy. Methods & clinical development 2021-12, Vol.23, p.582-596
Main Authors: Du, Zhicheng, Ng, Yu Yang, Zha, Shijun, Wang, Shu
Format: Article
Language:English
Subjects:
acute myeloid leukemia
IL-15
K562 APCs
NKG2D CAR-NK cells
Original
PiggyBac transposon
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Summary:Promising progress has been made in adoptive transfer of allogeneic natural killer (NK) cells to treat relapsed or refractory acute myeloid leukemia (AML). In this regard, chimeric antigen receptor (CAR)-modification of NK cells is considered as a compelling approach to augment the specificity and cytotoxicity of NK cells against AML. Using a non-viral piggyBac transposon technology and human peripheral blood-derived primary NK cells, we generated CAR-NK cells to target NKG2D ligands and demonstrated their in vitro activity in lysing cancer cells expressing the ligands and in vivo efficacy in inhibiting tumor growth in a xenograft KG-1 AML model. We further generated CAR-NK cells co-expressing transgenes for the NKG2D CAR and interleukin-15 (IL-15). The ectopic expression of IL-15 improved the in vitro and in vivo persistence of NKG2D CAR-NK cells, leading to enhanced in vivo tumor control and significant prolongation of mouse survival in the KG-1 AML model. Collectively, our findings demonstrate the ectopic expression of IL-15 as an important means to improve the antileukemic activity of NKG2D CAR-NK cells. Our study further illustrates the feasibility of using the piggyBac non-viral platform as an efficient and cost-effective way for CAR-NK cell manufacturing. [Display omitted] With a non-viral piggyBac transposon system, IL-15 armored NKG2D CAR-NK cells were generated from human PBMCs. These cells displayed superior persistence and anti-AML activity both in vitro and in vivo as compared with NKG2D CAR-NK cells without IL-15.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2021.10.014