Ligand-based adoptive T cell targeting CA125 in ovarian cancer

作者：Haihong Zhao, Lina Wu, Jiemin Dai, Ke Sun, Zhenguo Zi, Junhua Guan, Liwen Zhang · 发表于：Journal of Translational Medicine · 年份：2023 · DOI：10.1186/s12967-023-04271-8 · 被引用次数：27 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

BACKGROUND: Ovarian cancer (OC) is a highly aggressive gynecological malignancy prevalent worldwide. Most OC cases are typically diagnosed at advanced stages, which has led to a 5-year overall survival rate of less than 35% following conventional treatment. Furthermore, immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of patients with OC, and CAR-T therapy has also demonstrated modest results owing to inadequate T cell infiltration. Therefore, novel strategies must be developed to enhance T cell persistence and trafficking within the OC tumor microenvironment. METHODS: In this study, we developed a novel adoptive T-cell therapy for ovarian cancer based on a chimeric antigen receptor structure. We used a ligand-receptor binding motif to enhance the therapeutic effect of targeting CA125. Since mesothelin can naturally bind to CA125 with high affinity, we concatenated the core-binding fragment of mesothelin with the 4-1BB and CD3ζ signal fragments to assemble a novel CA125-targeting chimeric receptor (CR). The CAR structure targeting CA125 derived from the 4H11 antibody was also constructed. CR- and CAR-encoding RNA were electroporated into T cells to evaluate their antitumor activity both in vitro and in vivo. RESULTS: While CR-T or CAR-T cells exhibited moderate activity against two ovarian cancer cell lines, T cells co-expressing CR and CAR exhibited a superior killing effect compared to T cells expressing either CR or CAR alone. Furthermore, up...