Abstract
Simple Summaryc-Met is known to be overexpressed in gastric cancers. Here, we developed anti-c-Met CAR T cell and measured its anti-tumor efficacy in vitro and in vivo. Our anti c-Met CAR T cells have shown selective killing of c-Met overexpressed gastric cancer cells. Based on our results, we suggest that anti-c-Met CAR T cell therapy could be effective for gastric cancer patients.Chimeric antigen receptor (CAR) technology has been highlighted in recent years as a new therapeutic approach for cancer treatment. Although the impressive efficacy of CAR-based T cell adoptive immunotherapy has been observed in hematologic cancers, limited effect has been reported on solid tumors. Approximately 20% of gastric cancer (GC) patients exhibit a high expression of c-Met. We have generated an anti c-Met CAR construct that is composed of a single-chain variable fragment (scFv) of c-Met antibody and signaling domains consisting of CD28 and CD3ζ. To test the CAR construct, we used two cell lines: the Jurkat and KHYG-1 cell lines. These are convenient cell lines, compared to primary T cells, to culture and to test CAR constructs. We transduced CAR constructs into Jurkat cells by electroporation. c-Met CAR Jurkat cells secreted interleukin-2 (IL-2) only when incubated with c-Met positive GC cells. To confirm the lytic function of CAR, the CAR construct was transduced into KHYG-1, a NK/T cell line, using lentiviral particles. c-Met CAR KHYG-1 showed cytotoxic effect on c-Met positive GC cells, while c-Met negative GC cell lines were not eradicated by c-Met CAR KHYG-1. Based on these data, we created c-Met CAR T cells from primary T cells, which showed high IL-2 and IFN-γ secretion when incubated with the c-Met positive cancer cell line. In an in vivo xenograft assay with NSG bearing MKN-45, a c-Met positive GC cell line, c-Met CAR T cells effectively inhibited the tumor growth of MKN-45. Our results show that the c-Met CAR T cell therapy can be effective on GC.
Highlights
Research on Chimeric antigen receptor (CAR) T cell therapy has become quite active since CAR T cells targetingCD19 have shown an impressive response rate in patients with B-cell acute lymphoblastic leukemia (B-ALL) [1–6]
Our results show that the c-Met CAR T cell therapy can be effective on gastric cancer (GC)
Because c-Met overexpression occurs most often in GC compared to other cancer types, we thought that c-Met CAR T cell therapy against GC could be successful
Summary
Research on CAR T cell therapy has become quite active since CAR T cells targeting. CD19 have shown an impressive response rate in patients with B-cell acute lymphoblastic leukemia (B-ALL) [1–6]. CAR is composed of an scFv domain for antigen recognition, a co-stimulatory domain, and a CD3ζ signaling domain for T cell activation. Abnormal signaling pathway caused by c-Met overexpression is involved in cell survival, proliferation, migration, and angiogenesis, leading to tumor progression, invasion, metastasis, and recurrence [24]. For this reason, c-Met is regarded as a potent target for cancer treatment, and various small molecules of c-Met inhibitors are being developed [25,26]. Because c-Met overexpression occurs most often in GC compared to other cancer types, we thought that c-Met CAR T cell therapy against GC could be successful. We tested c-Met CAR T cells on various gastric cancer cell lines in this study. Our c-Met CAR T cell exhibited an anti-tumor effect against c-Met overexpressing GC in vitro and in vivo
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