Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells

Blood. 2021 Feb 4;137(5):624-636. doi: 10.1182/blood.2020007748.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Antigens, CD19
  • CD19 molecule, human
  • IL15 protein, human
  • Immune Checkpoint Inhibitors
  • Interleukin-15
  • Neoplasm Proteins
  • Receptors, Chimeric Antigen
  • Suppressor of Cytokine Signaling Proteins
  • cytokine inducible SH2-containing protein
  • AKT1 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt