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

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 hematologic...

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Bibliographic Details
Published in:Blood Vol. 136; no. 10; p. 1155
Main Authors: Fultang, Livingstone, Booth, Sarah, Yogev, Orli, Martins da Costa, Barbara, Tubb, Vanessa, Panetti, Silvia, Stavrou, Victoria, Scarpa, Ugo, Jankevics, Andris, Lloyd, Gavin, Southam, Andrew, Lee, Steven P, Dunn, Warwick B, Chesler, Louis, Mussai, Francis, De Santo, Carmela
Format: Journal Article
Language:English
Published: United States 03.09.2020
Subjects:
Animals
Apoptosis
Arginine - metabolism
Argininosuccinate Synthase - genetics
Argininosuccinate Synthase - metabolism
Cell Proliferation
Humans
Immunotherapy, Adoptive - methods
Leukemia, Myeloid, Acute - immunology
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Leukemia, Myeloid, Acute - therapy
Metabolic Engineering - methods
Mice
Mice, Nude
Neuroblastoma - immunology
Neuroblastoma - metabolism
Neuroblastoma - pathology
Neuroblastoma - therapy
Ornithine Carbamoyltransferase - genetics
Ornithine Carbamoyltransferase - metabolism
Receptors, Chimeric Antigen - chemistry
Receptors, Chimeric Antigen - immunology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
T-Lymphocytes - transplantation
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
ISSN:1528-0020, 1528-0020
Online Access:Get more information
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Summary: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.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood.2019004500