Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy
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.
Article Details
Authors (28)
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
City of Hope National Medical Center, Duarte, CA
Dat Ngo
Ibrahim Aldoss
Stephen J. Forman
City of Hope National Medical Center, Duarte, CA
Xiuli Wang
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences