Intraperitoneal immunotherapy with T cells stably and transiently expressing anti-EpCAM CAR in xenograft models of peritoneal carcinomatosis
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Wei Xia Ang1,2,*, Zhendong Li1,*, Zhixia Chi1, Shou-Hui Du1, Can Chen3, Johan C.K. Tay1, Han Chong Toh4, John E. Connolly5, Xue Hu Xu6, Shu Wang1,2
1Department of Biological Sciences, National University of Singapore 117543, Singapore
2Institute of Bioengineering and Nanotechnology 138669, Singapore
3Tessa Therapeutics, Pte Ltd., 239351, Singapore
4Division of Medical Oncology, National Cancer Centre, 169610, Singapore
5Programme in Translational Immunology, Institute for Molecular and Cell Biology 138648, Singapore
6Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
*The authors contributed equally to these work
Shu Wang, email: [email protected]
Keywords: peritoneal carcinomatosis, EpCAM, chimeric antigen receptor, T lymphocytes, adoptive immunotherapy
Received: June 16, 2016 Accepted: January 03, 2017 Published: January 10, 2017
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.
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