Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells.
Blood
; 137(5): 624-636, 2021 02 04.
Article
in En
| 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Killer Cells, Natural
/
Immunotherapy, Adoptive
/
Interleukin-15
/
Suppressor of Cytokine Signaling Proteins
/
Fetal Blood
/
Neoplasm Proteins
Limits:
Animals
/
Humans
Language:
En
Journal:
Blood
Year:
2021
Document type:
Article