Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo.
10.1007/s13238-017-0384-8
- Author:
Yanjing SONG
1
;
Chuan TONG
2
;
Yao WANG
2
;
Yunhe GAO
1
;
Hanren DAI
2
;
Yelei GUO
2
;
Xudong ZHAO
1
;
Yi WANG
1
;
Zizheng WANG
3
;
Weidong HAN
4
;
Lin CHEN
5
Author Information
1. Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China.
2. Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China.
3. Medical School of Chinese PLA, Beijing, 100853, China.
4. Bio-therapeutic Department, Chinese PLA General Hospital, Beijing, 100853, China. hanwdrsw69@yahoo.com.
5. Department of General Surgery, Chinese PLA General Hospital, Beijing, 100853, China. chenlinbj@vip.sina.com.
- Publication Type:Journal Article
- Keywords:
CD137;
HER2;
cancer stem cell;
chimeric antigen receptor;
gastric cancer;
immunotherapy
- MeSH:
Animals;
Humans;
Mice;
Mice, Inbred BALB C;
Mice, Nude;
Neoplasms, Experimental;
immunology;
pathology;
therapy;
Receptor, ErbB-2;
immunology;
Receptors, Antigen, T-Cell;
immunology;
Stomach Neoplasms;
immunology;
pathology;
therapy;
Tumor Cells, Cultured
- From:
Protein & Cell
2018;9(10):867-878
- CountryChina
- Language:English
-
Abstract:
Human epidermal growth factor receptor 2 (HER2) proteins are overexpressed in a high proportion of gastric cancer (GC) cases and affect the maintenance of cancer stem cell (CSC) subpopulations, which are used as targets for the clinical treatment of patients with HER2-positive GC. Despite improvements in survival, numerous HER2-positive patients fail treatment with trastuzumab, highlighting the need for more effective therapies. In this study, we generated a novel type of genetically modified human T cells, expressing a chimeric antigen receptor (CAR), and targeting the GC cell antigen HER2, which harbors the CD137 and CD3ζ moieties. Our findings show that the expanded CAR-T cells, expressing an increased central memory phenotype, were activated by the specific recognition of HER2 antigens in an MHC-independent manner, and effectively killed patient-derived HER2-positive GC cells. In HER2-positive xenograft tumors, CAR-T cells exhibited considerably enhanced tumor inhibition ability, long-term survival, and homing to targets, compared with those of non-transduced T cells. The sphere-forming ability and in vivo tumorigenicity of patient-derived gastric cancer stem-like cells, expressing HER2 and the CD44 protein, were also inhibited. Our results support the future development and clinical application of this adoptive immunotherapy in patients with HER2-positive advanced GC.
