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

TL;DR

This study explores how differences in metabolism between short- and long-term responders to CAR T cell therapy may affect treatment outcomes in B-cell leukemia patients.

Contribution

The study identifies immunometabolic differences in CAR T cells from long-term responders and proposes a strategy to enhance their anti-tumor activity.

Findings

Long-term responders have CAR T cells with higher oxidative phosphorylation and fatty acid oxidation.

mTOR inhibition during manufacturing improves CAR T cell anti-tumor activity.

Bone marrow microenvironment supports metabolic plasticity in long-term responders.

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.

Most patients with B-cell leukemia respond to chimeric antigen receptor T cell (CAR T) therapy, yet many relapse due to loss of CAR T function. Here, the authors show that the metabolism of CAR T from short- and long-term responders is different, which may explain why CAR T lose functionality.

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