靶向 c-Met 的 CAR-T 细胞在体外和体内抑制肝细胞癌细胞

c-Met is a hepatocyte growth factor receptor overexpressed in many tumors such as hepatocellular carcinoma (HCC).

Therefore, c-Met may serve as a promising target for HCC immunotherapy. Modifying T cells to express c-Met-specific chimeric antigen receptor (CAR) is an attractive strategy in treating c-Met-positive HCC.

This study aimed to systematically evaluate the inhibitory effects of 2 nd - and 3 rd -generation c-Met CAR-T cells on hepatocellular carcinoma (HCC) cells.

Here, 2 nd - and 3 rd -generation c-Met CARs containing an anti-c-Met single-chain variable fragment (scFv) as well as the CD28 signaling domain and CD3 (c-Met-28-3 ), the CD137 signaling domain and CD3 (c-Met-137-3 ), or the CD28 and CD137 signaling domains and CD3 (c-Met-28-137-3 ) were constructed, and their abilities to target c-Met-positive HCC cells were evaluated in vitro and in vivo .

All c-Met CARs were stably expressed on T cell membrane, and c-Met CAR-T cells aggregated around c-Met-positive HCC cells and specifically killed them in vitro . c-Met-28-137-3 CAR-T cells secreted more interferon-gamma (IFN- ) and interleukin 2 (IL-2) than c-Met-28-3 CAR-T cells and c-Met-137-3 CAR-T cells. Compared with c-Met low-expressed cells, c-Met CAR-T cells secreted more cytokines when co-cultured with c-Met high-expressed cells.

Moreover, c-Met-28-137-3 CAR-T cells eradicated HCC more effectively in xenograft tumor models compared with the control groups.

This study suggests that 3 rd -generation c-Met CAR-T cells are more effective in inhibiting c-Met-positive HCC cells than 2 nd -generation c-Met CAR-T cells, thereby providing a promising therapeutic intervention for c-Met-positive HCC.