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

Intraperitoneal immunotherapy with T cells stably and transiently expressing anti-EpCAM CAR in xenograft models of peritoneal carcinomatosis.

Author information

1
Department of Biological Sciences, National University of Singapore 117543, Singapore.
2
Institute of Bioengineering and Nanotechnology 138669, Singapore.
3
Tessa Therapeutics, Pte Ltd., 239351, Singapore.
4
Division of Medical Oncology, National Cancer Centre, 169610, Singapore.
5
Programme in Translational Immunology, Institute for Molecular and Cell Biology 138648, Singapore.
6
Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.

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

PMID:
28088790
PMCID:
PMC5355119
DOI:
10.18632/oncotarget.14592
[Indexed for MEDLINE]
Free PMC Article

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