Intraperitoneal Immunotherapy With T Cells Stably and Transiently Expressing anti-EpCAM CAR in Xenograft Models of Peritoneal Carcinomatosis

Oncotarget. 2017 Feb 21;8(8):13545-13559. doi: 10.18632/oncotarget.14592.

Abstract

The epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of tumor types, including peritoneal carcinomatosis (PC) from gastrointestinal and gynecological malignancies. To develop a chimeric antigen receptor T (CART) cell therapy approach to treat patients with end-stage PC, we constructed third generation CARs specific to EpCAM using the 4D5MOC-B single chain variable fragment. CART cells were generated with lentiviral transduction and exhibited specific in vitro killing activity against EpCAM-positive human ovarian and colorectal cancer cells. A single intraperitoneal injection of the CART cells eradicated established ovarian xenografts and resulted in significantly prolonged animal survival. Since EpCAM is also expressed on normal epithelium, anti-EpCAM CART cells were generated by mRNA electroporation that display a controlled cytolytic activity with a limited CAR expression duration. Multiple repeated infusions of these RNA CAR-modified T cells delayed disease progression in immunodeficient mice bearing well-established peritoneal ovarian and colorectal xenografts. Thus, our study demonstrates the effectiveness of using anti-EpCAM CAR-expressing T cells for local treatment of PC in mice. The possibility of using this approach for clinical treatment of EpCAM-positive gastrointestinal and gynecological malignancies warrants further validation.

Keywords: EpCAM; T lymphocytes; adoptive immunotherapy; chimeric antigen receptor; peritoneal carcinomatosis.

MeSH terms

  • Animals
  • Cytotoxicity, Immunologic
  • Epithelial Cell Adhesion Molecule / biosynthesis
  • Epithelial Cell Adhesion Molecule / genetics
  • Epithelial Cell Adhesion Molecule / immunology
  • Epithelial Cell Adhesion Molecule / metabolism*
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Peritoneal Neoplasms / immunology
  • Peritoneal Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / transplantation*
  • Xenograft Model Antitumor Assays

Substances

  • EPCAM protein, human
  • Epithelial Cell Adhesion Molecule
  • Receptors, Antigen, T-Cell