Abstract 1436: Development of a chimeric antigen receptor against glycosylated annexin A2 on ovarian tumors

Abstract

Chimeric antigen receptors (CARs) have been a significant focus of cancer therapeutic investigation in recent years, due to the remarkably effective responses observed in hematological cancers. However, the utility of CAR T cells has yet to be fully exhibited in solid tumours. One of the key challenges facing the treatment of solid tumors with CAR T cells is the dearth of viable antigen targets, which limits the expansion of this therapeutic space. Here, we describe how the anti-glycan monoclonal antibody 2448, which target annexin A2 on a number of ovarian and breast cancer cell lines, has been successfully reformatted as a CAR T cell construct. Messenger RNA (mRNA) encoding CAR(2448) was transfected into activated T cells, resulting in cytotoxicity and cytokine release upon co-incubation with target cells expressing annexin A2. While CAR(2448) variants with differing spacer chain lengths all mediated cytotoxicity against target cells compared to untransfected T cells, real-time target cell growth monitoring revealed that the long spacer CAR(2448) mediated higher levels of cytotoxicity, consistent with the membrane-proximal location of the annexin A2 target epitope. This optimization of CAR spacer length in the in vitro setting, using mRNA transfected T cells and real-time target cell growth monitoring, suggests that several aspects of CAR construction can be optimized in vitro, thereby lowering the threshold for CAR T cell development. These results suggest the potential for anti-glycan antibodies to be repurposed as CARs, and the development of CAR(2448) is currently being extended to lentiviral vectors for the purpose of developing long-term expressing CAR(2448) T cells, in anticipation of in vivo studies in murine models. This project was funded by the Agency for Science, Technology, and Research (A*STAR), Singapore and the A*STAR Graduate Academy (A*GA). Citation Format: Leonard W. Leong, Simeon Cua, Heng Liang Tan, Andre B. Choo. Development of a chimeric antigen receptor against glycosylated annexin A2 on ovarian tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1436.