靶向EDB-FN的CAR-T细胞在实体瘤治疗中的抗肿瘤和抗血管生成活性

Abstract

(1) Background: The lack of specific targets has slowed the progress of CAR-T in treating solid tumors. Recent studies have revealed that EDB-FN (fibronectin extra domain B) may be an effective target for CAR-T treatment of solid tumors; EDB-FN is expressed in tumor and embryonic tissues, and antibody–cytokine fusion proteins targeting EDB-FN have been developed. However, the therapeutic effects of BBz CAR-engineered T-cells targeting EDB-FN in solid tumors have not been evaluated. (2) Results: In this study, we constructed a BBz CAR construct targeting EDB-FN, and the CAR molecule was expressed on the surface of T-cells by lentiviral transduction. In vitro, CAR-T-cells can be activated to express perforin and granzyme and lyse EDB-positive cells (U-87 MG cells, A549 cells, and HUVECs) and have no toxicity to EDB-negative cells (MCF-7). Compared to T-cells, CAR-T-cells can release cytokines after coculture with EDB-positive cell lines. In vivo, CAR-T-cells inhibited the progression of U-87 MG subcutaneous tumors and significantly reduced the blood vessel density in tumor tissue compared to T-cells, without obvious toxicity to mouse tissues and organs. Furthermore, CAR-T-cells overexpressing BiTE targeting EDB-FN can significantly improve their antitumor activity in vitro. (3) Conclusions: These results demonstrate that CAR-T-cells have specific antitumor and angiogenic activities in vivo and in vitro, suggesting that EDB-FN may be a potential solid tumor target for CAR-T therapy.Keywords:fibronectin extra domain B;solid tumors;CAR-T-cells