Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells<i> in vitro</i> and xenotransplanted tumors <i>in vivo</i>

doi:10.1007/s13238-017-0384-8

Protein Cell

2018, Vol. 9

Issue (10) : 867-878 https://doi.org/10.1007/s13238-017-0384-8

RESEARCH ARTICLE

Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo

Yanjing Song^1,², Chuan Tong³, Yao Wang³, Yunhe Gao^1,², Hanren Dai³, Yelei Guo³, Xudong Zhao^1,², Yi Wang^1,², Zizheng Wang², Weidong Han^3,⁴(

), Lin Chen¹(

)

¹. Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
². Medical School of Chinese PLA, Beijing 100853, China
³. Bio-therapeutic Department, Chinese PLA General Hospital, Beijing 100853, China
⁴. Molecular & Immunology Department, Chinese PLA General Hospital, Beijing 100853, China

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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 andCD3ζ 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.

Keywords chimeric antigen receptor HER2 gastric cancer cancer stem cell CD137 immunotherapy

Corresponding Author(s): Weidong Han,Lin Chen

Issue Date: 18 October 2018

Cite this article:

Yanjing Song,Chuan Tong,Yao Wang, et al. Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo[J]. Protein Cell, 2018, 9(10): 867-878.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-017-0384-8
https://academic.hep.com.cn/pac/EN/Y2018/V9/I10/867

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