Engineered T lymphocytes eliminate lung metastases in models of pancreatic cancer

Abstract

// Qiang Sun 1 , Shixin Zhou 1 , Jingjing Zhao 1 , Changwen Deng 1 , Ruidi Teng 1 , Yiding Zhao 1 , Jiajia Chen 1 , Jiebin Dong 1 , Ming Yin 2 , Yun Bai 1 , Hongkui Deng 1, 3, 4 and Jinhua Wen 1 1 Department of Cell Biology and Stem Cell Research Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China 2 Beijing Vitalstar Biotechnology Co., Ltd., Beijing, China 3 The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China 4 Shenzhen Stem Cell Engineering Laboratory, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China Correspondence to: Jinhua Wen, email: jhwen@bjmu.edu.cn Hongkui Deng, email: hongkui_deng@pku.edu.cn Yun Bai, email: baiyun@bjmu.edu.cn Keywords: adoptive cell therapy; mesothelin; CAR; lung metastasis Received: May 16, 2017      Accepted: November 13, 2017      Published: January 10, 2018 ABSTRACT Pancreatic cancer is known as one of the most lethal cancers in the world. A majority of advanced stage pancreatic cancer patients are diagnosed with distant metastasis and given poor prognoses, calling for a better therapeutic option. Mesothelin, which is overexpressed in pancreatic cancer and other solid tumors, is a potential target for pancreatic cancer immunotherapy. Adoptive transfer of T cells engineered with chimeric antigen receptors (CART cells) was effective for treating CD19-positive leukemia, but it is more difficult for CART cells to eliminate solid tumors. Because distal metastasis is an important malignant behavior of solid tumors, we investigated whether meso-CART cells exert anti-tumor effects against distant metastases. After expressing meso-CAR in human primary T lymphocytes, the resultant meso-CART cells released cytokines in response to and exhibited cytolytic effects on mesothelin-positive tumor cells in vitro . Injection of meso-CART cells into tumor-bearing mice moderately delayed subcutaneous tumor growth and eliminated lung metastases. This is the first study to show that meso-CART cells are effective against lung metastases induced by intravenous injection of pancreatic tumor cells. Our results suggest that meso-CART cells may be an effective clinical treatment for mesothelin-positive primary and metastatic tumors in pancreatic cancer patients.