Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity.
Blood
; 136(10): 1155-1160, 2020 09 03.
Article
em En
| MEDLINE
| ID: mdl-32573723
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ornitina Carbamoiltransferase
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Arginina
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Argininossuccinato Sintase
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Linfócitos T
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Leucemia Mieloide Aguda
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Imunoterapia Adotiva
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Neuroblastoma
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article