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

Autor:	Daher M; Department of Stem Cell Transplantation and Cellular Therapy and., Basar R; Department of Stem Cell Transplantation and Cellular Therapy and., Gokdemir E; Department of Stem Cell Transplantation and Cellular Therapy and., Baran N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Uprety N; Department of Stem Cell Transplantation and Cellular Therapy and., Nunez Cortes AK; Department of Stem Cell Transplantation and Cellular Therapy and., Mendt M; Department of Stem Cell Transplantation and Cellular Therapy and., Kerbauy LN; Department of Stem Cell Transplantation and Cellular Therapy and.; Department of Stem Cell Transplantation and Cellular Therapy, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.; Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of Sao Paulo, Sao Paulo, Brazil., Banerjee PP; Department of Stem Cell Transplantation and Cellular Therapy and., Shanley M; Department of Stem Cell Transplantation and Cellular Therapy and., Imahashi N; Department of Stem Cell Transplantation and Cellular Therapy and., Li L; Department of Stem Cell Transplantation and Cellular Therapy and., Lim FLWI; Department of Stem Cell Transplantation and Cellular Therapy and., Fathi M; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX., Rezvan A; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX., Mohanty V; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX., Shen Y; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX., Shaim H; Department of Stem Cell Transplantation and Cellular Therapy and., Lu J; Department of Stem Cell Transplantation and Cellular Therapy and., Ozcan G; Department of Stem Cell Transplantation and Cellular Therapy and., Ensley E; Department of Stem Cell Transplantation and Cellular Therapy and., Kaplan M; Department of Stem Cell Transplantation and Cellular Therapy and., Nandivada V; Department of Stem Cell Transplantation and Cellular Therapy and., Bdiwi M; Department of Stem Cell Transplantation and Cellular Therapy and., Acharya S; Department of Stem Cell Transplantation and Cellular Therapy and., Xi Y; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX., Wan X; Department of Stem Cell Transplantation and Cellular Therapy and., Mak D; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Liu E; Department of Stem Cell Transplantation and Cellular Therapy and., Jiang XR; Department of Stem Cell Transplantation and Cellular Therapy and., Ang S; Department of Stem Cell Transplantation and Cellular Therapy and., Muniz-Feliciano L; Department of Stem Cell Transplantation and Cellular Therapy and., Li Y; Department of Stem Cell Transplantation and Cellular Therapy and., Wang J; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX., Kordasti S; System Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom., Petrov N; System Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom., Varadarajan N; Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX., Marin D; Department of Stem Cell Transplantation and Cellular Therapy and., Brunetti L; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX., Skinner RJ; C.T. Bauer College of Business, University of Houston, Houston, TX., Lyu S; C.T. Bauer College of Business, University of Houston, Houston, TX., Silva L; C.T. Bauer College of Business, University of Houston, Houston, TX., Turk R; Integrated DNA Technologies, Coralville, IA., Schubert MS; Integrated DNA Technologies, Coralville, IA., Rettig GR; Integrated DNA Technologies, Coralville, IA., McNeill MS; Integrated DNA Technologies, Coralville, IA., Kurgan G; Integrated DNA Technologies, Coralville, IA., Behlke MA; Integrated DNA Technologies, Coralville, IA., Li H; Dana-Farber/Harvard Cancer Center, Boston, MA; and., Fowlkes NW; Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX., Chen K; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX., Konopleva M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Champlin RE; Department of Stem Cell Transplantation and Cellular Therapy and., Shpall EJ; Department of Stem Cell Transplantation and Cellular Therapy and., Rezvani K; Department of Stem Cell Transplantation and Cellular Therapy and.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 Feb 04; Vol. 137 (5), pp. 624-636.
DOI:	10.1182/blood.2020007748
Abstrakt:	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. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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