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

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.

SUBMITTER: Daher M

PROVIDER: S-EPMC7869185 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Daher May M Basar Rafet R Gokdemir Elif E Baran Natalia N Uprety Nadima N Nunez Cortes Ana Karen AK Mendt Mayela M Kerbauy Lucila Nassif LN Banerjee Pinaki P PP Shanley Mayra M Imahashi Nobuhiko N Li Li L Lim Francesca Lorraine Wei Inng FLWI Fathi Mohsen M Rezvan Ali A Mohanty Vakul V Shen Yifei Y Shaim Hila H Lu Junjun J Ozcan Gonca G Ensley Emily E Kaplan Mecit M Nandivada Vandana V Bdiwi Mustafa M Acharya Sunil S Xi Yuanxin Y Wan Xinhai X Mak Duncan D Liu Enli E Jiang Xin Ru XR Ang Sonny S Muniz-Feliciano Luis L Li Ye Y Wang Jing J Kordasti Shahram S Petrov Nedyalko N Varadarajan Navin N Marin David D Brunetti Lorenzo L Skinner Richard J RJ Lyu Shangrong S Silva Leiser L Turk Rolf R Schubert Mollie S MS Rettig Garrett R GR McNeill Matthew S MS Kurgan Gavin G Behlke Mark A MA Li Heng H Fowlkes Natalie W NW Chen Ken K Konopleva Marina M Champlin Richard E RE Shpall Elizabeth J EJ Rezvani Katayoun K

Blood 20210201 5

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 eff ...[more]

PMID: 32902645

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Project description:Chimeric antigen receptor (CAR) T and CAR NK cell therapies opened new avenues for cancer treatment. Although original successes of CAR T and CAR NK cells for the treatment of hematological malignancies were extraordinary, several obstacles have since been revealed, in particular their use for the treatment of solid cancers. The tumor microenvironment (TME) is competing for nutrients with T and NK cells and their CAR-expressing counterparts, paralyzing their metabolic effective and active states. Consequently, this can lead to alterations in their anti-tumoral capacity and persistence in vivo. High glucose uptake and the depletion of key amino acids by the TME can deprive T and NK cells of energy and building blocks, which turns them into a state of anergy, where they are unable to exert cytotoxic activity against cancer cells. This is especially true in the context of an immune-suppressive TME. In order to re-invigorate the T, NK, CAR T and CAR NK cell-mediated antitumor response, the field is now attempting to understand how metabolic pathways might change T and NK responses and functions, as well as those from their CAR-expressing partners. This revealed ways to metabolically rewire these cells by using metabolic enhancers or optimizing pre-infusion in vitro cultures of these cells. Importantly, next-generation CAR T and CAR NK products might include in the future the necessary metabolic requirements by improving their design, manufacturing process and other parameters. This will allow the overcoming of current limitations due to their interaction with the suppressive TME. In a clinical setting, this might improve their anti-cancer effector activity in synergy with immunotherapies. In this review, we discuss how the tumor cells and TME interfere with T and NK cell metabolic requirements. This may potentially lead to therapeutic approaches that enhance the metabolic fitness of CAR T and CAR NK cells, with the objective to improve their anti-cancer capacity.

Dataset Information

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

Publications

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

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