Improved CAR-T cell activity associated with increased mitochondrial function primed by galactose

Golda Gross, Suha Alkadieri, Amilia Meir, Orit Itzhaki, Yarden Aharoni-Tevet, Shahar Ben Yosef, Angi Zenab, Liat Shbiro, Amos Toren, Tal Yardeni, Elad Jacoby

Research output: Contribution to journalArticlepeer-review

Abstract

CD19 CAR-T cells have led to durable remissions in patients with refractory B-cell malignancies; nevertheless, most patients eventually relapse in the long term. Many interventions aimed at improving current products have been reported, with a subset of them focusing on a direct or indirect link to the metabolic state of the CAR-T cells. We assessed clinical products from an ongoing clinical trial utilizing CD19-28z CAR-T cells from patients with acute lymphoblastic leukemia. CAR-T clinical products leading to a complete response had significantly higher mitochondrial function (by oxygen consumption rate) irrespective of mitochondrial content. Next, we replaced the carbon source of the media from glucose to galactose to impact cellular metabolism. Galactose-containing media increased mitochondrial activity in CAR-T cells, and improved in in-vitro efficacy, without any consistent phenotypic change in memory profile. Finally, CAR-T cells produced in galactose-based glucose-free media resulted in increased mitochondrial activity. Using an in-vivo model of Nalm6 injected mice, galactose-primed CAR-T cells significantly improved leukemia-free survival compared to standard glucose-cultured CAR-T cells. Our results prove the significance of mitochondrial metabolism on CAR-T cell efficacy and suggest a translational pathway to improve clinical products.

Original languageEnglish
JournalLeukemia
Early online date7 May 2024
DOIs
StatePublished - Jul 2024
Externally publishedYes

Bibliographical note

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© The Author(s), under exclusive licence to Springer Nature Limited 2024.

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