Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy
- Lior Goldberg
- Eric R. Haas
- Jiaqi Wu
- Bryan Garcia
- Ryan Urak
- Vibhuti Vyas
- Ruby Espinosa
- Tamara Munoz
- Shirley Bierkatz
- Khyatiben V. Pathak
- Nathaniel P. Hansen
- Patrick Pirrotte
- Jyotsana Singhal
- James L. Figarola
- Ricardo Zerda Noriega
- Zhuo Li
- Dasol Wi
- Erin Tanaka
- Ramon Klein Geltink
- Min-Hsuan Chen
- Xiwei Wu
- Jamie R. Wagner
- Jinny Paul
- Mary C. Clark
- Dat Ngo
- Ibrahim Aldoss
- Stephen J. Forman
- Xiuli Wang
2026-02-20
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.