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

Research output: Contribution to journalArticlepeer-review

Katy Rezvani

Original languageEnglish
Pages (from-to)624–636
Number of pages13
JournalBlood
Volume137
Issue number5
Early online date9 Sep 2020
DOIs
Accepted/In press29 Aug 2020
E-pub ahead of print9 Sep 2020
Published4 Feb 2021

Bibliographical note

Funding Information: Supported in part by the generous philanthropic support to The University of Texas MD Anderson Cancer Center Moonshot program, by grants from the Cancer Prevention and Research Institute of Texas (RP160693) and the National Institutes of Health, National Cancer Institute (1 R01 CA211044-01 and PO1 5P01CA148600-03) and by Cancer Center Support (CORE) grant CA016672 (to the Flow Cytometry and Cellular Imaging Facility and the A sequencing core facility at Anderson Cancer Center). The authors acknowledge the support of a Deutsche Knochen Mark Spenderdatei Mechtild Harf research grant and a Society for Immunotherapy of Cancer-Amgen Cancer Immunotherapy in Hematologic Malignancies fellowship award (M.D.). Publisher Copyright: © 2021 American Society of Hematology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Documents

  • Accepted version

    87430_1_art_file_436050_qg1rvb.pdf, 1 MB, application/pdf

    Uploaded date:11 Sep 2020

    Version:Accepted author manuscript

King's Authors

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.

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