期刊
BLOOD
卷 137, 期 5, 页码 624-636出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020007748
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资金
- University of Texas MD Anderson Cancer Center Moonshot program
- Cancer Prevention and Research Institute of Texas [RP160693]
- National Institutes of Health, National Cancer Institute [1 R01 CA211044-01, PO1 5P01CA148600-03]
- Cancer Center Support (CORE) [CA016672]
- Deutsche Knochen Mark Spenderdatei Mechtild Harf research grant
- Society for Immunotherapy of Cancer-Amgen Cancer Immunotherapy in Hematologic Malignancies fellowship award
The study combined targeting of CIS protein with CAR engineering of NK cells, leading to improved NK cell effector function and successful antitumor activity in a lymphoma mouse model. This approach represents a promising milestone in the development of next-generation NK cells for cancer immunotherapy.
Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation armored chimeric antigen receptor (CAR) engineering of cord blood-derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.
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