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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月20日

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  • 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

摘要

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.