Abstract 1772: Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer

Abstract

Abstract L1 cell adhesion molecule (L1CAM) is involved in cancer development and aberrantly expressed in various tumor. It is also associated with aggressive progression, metastasis, and poor prognosis. Public database, a Kaplan-Meier plotter (http://www.kmplot.com) shows that L1CAM high-expression significantly reduced survival of ovarian and gastric cancer patients. We developed a novel chimeric antigen receptor (CAR)-T cell targeted to L1CAM. A novel scFV candidate (Clone H8) to L1CAM was obtained by bio-panning of phage displaying human synthetic scFv fragments to human and mouse L1CAM proteins. H8 scFV was linked to IgD-IgG1 hinge, CD28 transmembrane domain, CD28 and ICOS co-stimulation domain, and CD3ζ domain, resulting in CX804 CAR-T. The efficacy of L1CAM CAR-T cells, CX804 showed correlation with the level of L1CAM in human ovarian and gastric cancer cells. CX804 exerted cytotoxicity toward 293T cells expressing human or mouse L1CAM protein. CX804 also reacted with L1CAM-positive ovarian SKOV3 cancer cell and gastric MKN-28 and AGS cancer cells and secreted T-cell activation cytokines, IFN-γ and TNF-α, in response to these cells. However, CX804 rarely lysed L1CAM-negative normal 293 cells and SNU-719 gastric cancer cells. Furthermore, L1CAM CAR-T cells dramatically lysed high L1CAM expressing patient derived cell (PDC) of gastric cancer compared with low L1CAM expressing PDC cell. Xenograft model of ovarian cancer was developed by intraperitoneal (IP) injecting SKOV3-Fluc cells into NOD/SCID or NSG mice. CAR-T cells were administrated via intravenous (IV) or IP route on 5 days after tumor inoculation. Administration of CX804 significantly decreased tumor burden and increased survival in mouse model of ovarian cancer. Route of administration significantly affected bio-distribution and antitumor effect of CX804 where antitumor activity of CX804 was only observed when CX804 were given IP, but not the IV route. Taken together, our results suggest that CX804 exerts potent and specific effect against L1CAM positive cancer cells in vitro and in vivo. Furthermore, we propose that newly established CAR-T cells targeting L1CAM facilitate therapy against L1CAM-positive ovarian and gastric cancer patients Citation Format: Xiumei Che, Un-Jung Yun, Seokwon Lee, Youngyoub Kim, Junshub Lee, Jina Chae, Jehee Suh, Eun-Ji Nam, Gun Min Kim, Hyoyoung Kim, Minkyu Jung. Development of a novel L1CAM-targeted CAR-T, CX804, and its therapeutic efficacy in ovarian and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1772.