期刊
ONCOTARGET
卷 8, 期 8, 页码 13545-13559出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14592
关键词
peritoneal carcinomatosis; EpCAM; chimeric antigen receptor; T lymphocytes; adoptive immunotherapy
资金
- Singapore Ministry of Health's National Medical Research Council [NMRC/CIRG/1367/2013, NMRC/CIRG/1406/2014]
- Science and Technology Planning Projects of Guangdong Province, China [2016B090918130]
- Institute of Bioengineering and Nanotechnology, Biomedical Research Council, Agency for Science, Technology and Research, Singapore
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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