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

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-017-0384-8) contains supplementary material, which is available to authorized users.

Driving better and safer HER2-specific CARs for cancer therapy

“…HER2 has been targeted with 2nd and 3rd generation CAR T cells in breast cancer [ 35 , 36 ], gastric cancer [ 37 ], glioblastoma [ 38 ], sarcoma [ 39 ], ovarian cancer [ 40 ], and osteosarcoma [ 41 ].The majority of studies have clearly demonstrated that the incorporation of co-stimulation molecules, such as CD28, 4-1BB, OX-40, ICOS, or CD27 [ 30 , 36 , 42 – 44 ] into CAR constructs offers better therapeutic benefit in preclinical and clinical settings. In one of these studies, Zhao et al [ 36 ] found decreased transgene expression and increased apoptotic/dead cells of Herceptin-based 4D5 HER2 CARs with or without CD28 costimulation moiety.…”

Establishment of a Human Gastric Cancer Xenograft Model in Immunocompetent Mice Using the Microcarrier‐6

“…Animal models have been extensively used to study the pathogenesis and metastatic mechanisms of gastric cancer and play an extremely important role in the evaluation of the efficacy and toxicity of therapeutic drugs [8][9][10]. At present, gastric cancer animal models mainly include the following: the induction model, the transplantation model, and the genetic engineering model [11].…”

CD19-CAR-T Cells Bearing a KIR/PD-1-Based Inhibitory CAR Eradicate CD19+HLA-C1− Malignant B Cells While Sparing CD19+HLA-C1+ Healthy B Cells

“…The cytotoxicity of iKP-19 CAR-T cells or CD19-CAR-T cells against Daudi cells or normal B cells was evaluated by using a standard lactic dehydrogenase (LDH) release assay (Promega, Madison, WI, USA) as described earlier by Song et al [ 50 ]. Briefly, target cells were seeded at a density of 10 4 cells per well in 96 well plate in a triplicate manner.…”