title: Intraperitoneal immunotherapy with T cells stably and transiently expressing anti-EpCAM CAR in xenograft models of peritoneal carcinomatosis.
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.
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.|Institute of Bioengineering and Nanotechnology 138669, Singapore.
authors.forename: Wei Xia
authors.initials: WX
authors.lastname: Ang
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.
authors.forename: Shou-Hui
authors.initials: SH
authors.lastname: Du
authors.affiliation: Tessa Therapeutics, Pte Ltd., 239351, Singapore.
authors.forename: Can
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.
authors.forename: Johan C K
authors.initials: JC
authors.lastname: Tay
authors.affiliation: Division of Medical Oncology, National Cancer Centre, 169610, Singapore.
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.affiliation: Programme in Translational Immunology, Institute for Molecular and Cell Biology 138648, Singapore.
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
authors.affiliation: Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.
authors.forename: Xue Hu
authors.initials: XH
authors.lastname: Xu
authors.affiliation: Department of Biological Sciences, National University of Singapore 117543, Singapore.|Institute of Bioengineering and Nanotechnology 138669, Singapore.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D000071858:Epithelial Cell Adhesion Molecule / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D011948:Receptors, Antigen, T-Cell
keywords: EpCAM; T lymphocytes; adoptive immunotherapy; chimeric antigen receptor; peritoneal carcinomatosis