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Blood ; 137(5): 624-636, 2021 02 04.
Article in English | MEDLINE | ID: mdl-32902645

ABSTRACT

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.


Subject(s)
Fetal Blood/cytology , Immunotherapy, Adoptive , Interleukin-15/genetics , Killer Cells, Natural/drug effects , Neoplasm Proteins/antagonists & inhibitors , Suppressor of Cytokine Signaling Proteins/antagonists & inhibitors , Aerobiosis , Animals , Antigens, CD19/immunology , Burkitt Lymphoma/pathology , Burkitt Lymphoma/therapy , CRISPR-Cas Systems , Cell Line, Tumor , Gene Knockout Techniques , Glycolysis , Humans , Immune Checkpoint Inhibitors/pharmacology , Interleukin-15/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Killer Cells, Natural/transplantation , Mechanistic Target of Rapamycin Complex 1/physiology , Mice , Neoplasm Proteins/genetics , Neoplasm Proteins/physiology , Proto-Oncogene Proteins c-akt/physiology , Receptors, Chimeric Antigen , Signal Transduction/physiology , Suppressor of Cytokine Signaling Proteins/genetics , Suppressor of Cytokine Signaling Proteins/physiology , Xenograft Model Antitumor Assays
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