TY - JOUR
T1 - Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells
AU - Daher, May
AU - Basar, Rafet
AU - Gokdemir, Elif
AU - Baran, Natalia
AU - Uprety, Nadima
AU - Nunez Cortes, Ana Karen
AU - Mendt, Mayela
AU - Kerbauy, Lucila Nassif
AU - Banerjee, Pinaki P.
AU - Shanley, Mayra
AU - Imahashi, Nobuhiko
AU - Li, Li
AU - Lim, Francesca Lorraine Wei Inng
AU - Fathi, Mohsen
AU - Rezvan, Ali
AU - Mohanty, Vakul
AU - Shen, Yifei
AU - Shaim, Hila
AU - Lu, Junjun
AU - Ozcan, Gonca
AU - Ensley, Emily
AU - Kaplan, Mecit
AU - Nandivada, Vandana
AU - Bdiwi, Mustafa
AU - Acharya, Sunil
AU - Xi, Yuanxin
AU - Wan, Xinhai
AU - Mak, Duncan
AU - Liu, Enli
AU - Jiang, Xin Ru
AU - Ang, Sonny
AU - Muniz-Feliciano, Luis
AU - Li, Ye
AU - Wang, Jing
AU - Kordasti, Shahram
AU - Petrov, Nedyalko
AU - Varadarajan, Navin
AU - Marin, David
AU - Brunetti, Lorenzo
AU - Skinner, Richard J.
AU - Lyu, Shangrong
AU - Silva, Leiser
AU - Turk, Rolf
AU - Schubert, Mollie S.
AU - Rettig, Garrett R.
AU - McNeill, Matthew S.
AU - Kurgan, Gavin
AU - Behlke, Mark A.
AU - Li, Heng
AU - Fowlkes, Natalie W.
AU - Chen, Ken
AU - Konopleva, Marina
AU - Champlin, Richard E.
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/2/4
Y1 - 2021/2/4
N2 - 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. Key Points: • CRISPR-Cas9 CISH deletion enhances the metabolic fitness and antitumor activity of armored IL-15–secreting CB-derived CAR-NK cells.
AB - 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. Key Points: • CRISPR-Cas9 CISH deletion enhances the metabolic fitness and antitumor activity of armored IL-15–secreting CB-derived CAR-NK cells.
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U2 - 10.1182/blood.2020007748
DO - 10.1182/blood.2020007748
M3 - Article
C2 - 32902645
AN - SCOPUS:85100389627
SN - 0006-4971
VL - 137
SP - 624
EP - 636
JO - Blood
JF - Blood
IS - 5
ER -