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.
Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells / Daher, M.; Basar, R.; Gokdemir, E.; Baran, N.; Uprety, N.; Nunez Cortes, A. K.; Mendt, M.; Kerbauy, L. N.; Banerjee, P. P.; Shanley, M.; Imahashi, N.; Li, L.; Lim, F. L. W. I.; Fathi, M.; Rezvan, A.; Mohanty, V.; Shen, Y.; Shaim, H.; Lu, J.; Ozcan, G.; Ensley, E.; Kaplan, M.; Nandivada, V.; Bdiwi, M.; Acharya, S.; Xi, Y.; Wan, X.; Mak, D.; Liu, E.; Jiang, X. R.; Ang, S.; Muniz-Feliciano, L.; Li, Y.; Wang, J.; Kordasti, S.; Petrov, N.; Varadarajan, N.; Marin, D.; Brunetti, L.; Skinner, R. J.; Lyu, S.; Silva, L.; Turk, R.; Schubert, M. S.; Rettig, G. R.; Mcneill, M. S.; Kurgan, G.; Behlke, M. A.; Li, H.; Fowlkes, N. W.; Chen, K.; Konopleva, M.; Champlin, R. E.; Shpall, E. J.; Rezvani, K.. - In: BLOOD. - ISSN 0006-4971. - ELETTRONICO. - 137:5(2021), pp. 624-636. [10.1182/blood.2020007748]
Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells
Kordasti S.Formal Analysis
;Brunetti L.;
2021-01-01
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. Key Points: • CRISPR-Cas9 CISH deletion enhances the metabolic fitness and antitumor activity of armored IL-15–secreting CB-derived CAR-NK cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
