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

Goldberg, L.; Haas, E. R.; Wu, J.; Garcia, B.; Urak, R.; Vyas, V.; Espinosa, R.; Munoz, T.; Bierkatz, S.; PATHAK, K. V.; Hansen, N. P.; Pirrotte, P.; Singhal, J.; Figarola, J.; Noriega, R. Z.; Li, Z.; Wi, D.; Tanaka, E.; Klein Geltink, R. I.; Chen, M.-H.; Wu, X.; Wagner, J. R.; Paul, J.; Clark, M. C.; Ngo, D.; Aldoss, I.; Forman, S. J.; Wang, X.

doi:10.1101/2025.10.23.684261

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bioRxiv · 10.1101/2025.10.23.684261

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

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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. We applied 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) had 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 had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced 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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Goldberg, L., Haas, E. R., Wu, J., Garcia, B., Urak, R., Vyas, V., Espinosa, R., Munoz, T., Bierkatz, S., PATHAK, K. V., Hansen, N. P., Pirrotte, P., Singhal, J., Figarola, J., Noriega, R. Z., Li, Z., Wi, D., Tanaka, E., Klein Geltink, R. I., Chen, M.-H., Wu, X., Wagner, J. R., Paul, J., Clark, M. C., Ngo, D., Aldoss, I., Forman, S. J., Wang, X.. 2025-10-24. Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy. https://doi.org/10.1101/2025.10.23.684261

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