Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Livingstone Fultang, Sarah Booth, Orli Yogev, Barbara Martins da Costa, Vanessa Tubb, Silvia Panetti, Victoria Stavrou, Ugo Scarpa, Andris Jankevics, Gavin Lloyd, Andrew D Southam, Steven P. Lee, Warwick Dunn, Louis Chesler, Francis Jay Mussai, Carmela De Santo

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

Original languageEnglish
Pages (from-to)1155-1160
Number of pages6
Issue number10
Publication statusPublished - 3 Sept 2020

Bibliographical note

Funding Information:
This work was supported by Cancer Research UK, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children’s Hospital, and the alumni and donors to the University of Birmingham. This work was supported by Phenome Centre Birmingham (MR/M009157/1).

Publisher Copyright:
© 2020 by The American Society of Hematology

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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