Preclinical Evaluation of Chimeric Antigen Receptor-Modified T Cells Specific to Epithelial Cell Adhesion Molecule for Treating Colorectal Cancer

Hum Gene Ther. 2019 Apr;30(4):402-412. doi: 10.1089/hum.2018.229. Epub 2019 Mar 13.

Abstract

Chimeric antigen receptor-modified T cells (CAR-T cells) have emerged as a promising cancer immunotherapy for solid tumors. Epithelial cell adhesion molecule (EpCAM) is overexpressed in a variety of tumors and is recognized as a biomarker for circulating tumor cells and cancer stem cells, representing an attractive target for adoptive T-cell immunotherapy. This study generated third-generation CAR-T cells with redirected specificity to EpCAM (EpCAM CAR-T) by lentiviral vector. The study demonstrated that EpCAM CAR-T cells can elicit lytic cytotoxicity to target cells in an EpCAM-dependent manner and secrete cytotoxic cytokines, including interferon gamma and tumor necrosis factor alpha. Furthermore, adoptive transfer of EpCAM CAR-T cells significantly delayed tumor growth and formation in xenograft models. In addition, the safety evaluation showed that CAR-T cells have no systemic toxicity in mice. The data confirmed the antitumor ability and safety of CAR-T cells targeting EpCAM and may provide a new target for CAR-T cell therapies in treating solid tumors.

Keywords: EpCAM; cancer immunotherapy; chimeric antigen receptor; colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / therapy
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Epithelial Cell Adhesion Molecule / antagonists & inhibitors
  • Epithelial Cell Adhesion Molecule / immunology*
  • Humans
  • Immunophenotyping
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Mice
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers
  • Epithelial Cell Adhesion Molecule
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen