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

Blood. 2020 Sep 3;136(10):1155-1160. doi: 10.1182/blood.2019004500.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Receptors, Chimeric Antigen
  • Arginine
  • Ornithine Carbamoyltransferase
  • Argininosuccinate Synthase