What does this research mean for the field?

Pre-infusion CAR T cells of long-term responders in B-ALL exhibit enhanced oxidative phosphorylation and lower mTOR expression compared to short-term responders, which are associated with improved anti-tumor activity. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The research aims to identify immunometabolic characteristics that predict long-term responses in leukemia patients treated with CD19 CAR T cell therapy.

February 22, 2026Open Access

Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy

Key Points

The research aims to identify immunometabolic characteristics that predict long-term responses in leukemia patients treated with CD19 CAR T cell therapy.
Analyzed pre- and post-infusion CAR T cells from leukemia patients.
Compared metabolic activity in long-term responders and short-term responders.
Monitored mTOR expression and mitochondrial features in CAR T cells.
Tested the effects of transient mTOR inhibition on CAR T cell metabolism and tumor activity.
Long-term responders exhibited increased oxidative phosphorylation and fatty acid oxidation pre-infusion.
Post-infusion CAR T cells showed high immunometabolic plasticity and mTOR-pS6 expression.
Transient mTOR inhibition during CAR T cell manufacture improved anti-tumor activity.

Abstract

Abstract Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. Herein, we apply an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) have increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR have high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induces metabolic reprogramming and enhances anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.

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