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

Author:

Fultang Livingstone1ORCID,Booth Sarah1,Yogev Orli2,Martins da Costa Barbara2,Tubb Vanessa1ORCID,Panetti Silvia1,Stavrou Victoria1,Scarpa Ugo1,Jankevics Andris3ORCID,Lloyd Gavin3ORCID,Southam Andrew3ORCID,Lee Steven P.1,Dunn Warwick B.3,Chesler Louis2,Mussai Francis1ORCID,De Santo Carmela1

Affiliation:

1. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom;

2. The Institute of Cancer Research, London, United Kingdom; and

3. School of Biosciences and Phenome Centre Birmingham and

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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