Abstract 3579: RegCAR-TTM: Enabling next-generation CAR-T therapy

Abstract

Abstract Chimeric Antigen Receptor (CAR) T-Cell Therapy has been emerging as a means of powerful cancer immunotherapy with its exceptional therapeutic efficacy, however, the full potential of CAR-T therapy is hampered by its severe side effects. Thus, CAR-T therapy that is controllable for optimal efficacy and safety is in need developing. To enable controllable CAR-T therapy, we have established a technology platform, RegCAR-TTM. In RegCAR-TTM, aptazymes are generated by in vitro selection/evolution of combinatory nucleic acid libraries and are used as molecular switches for controlling CAR expression. Aptazymes are RNA molecules consisting of an aptamer module and a ribozyme module, in which ribozyme self-cleavage can be allosterically regulated by the aptamer-ligand (e.g. a small molecule drug) interaction. With an aptazyme switch incorporated into the untranslated region (UTR) of a CAR gene, CAR expression can be temporally and dose-dependently controlled at mRNA level by a ligand, which may result in controllability of CAR-T efficacy and safety. Using RegCAR-TTM technology, we have generated aptazyme switches responsive to FDA-approved small molecules drugs with IC50 at micromolar level. Thus, next generation CAR-T therapies with aptazyme switches would be controllable by safe oral small molecules drugs. In conclusion, we have developed a technology platform (RegCAR-TTM) to generate aptazyme switches for enabling controllable CAR-T therapy. Citation Format: Xu Zhang, Ke Tang, Qingxuan Song, Si Chen, christopher Kasbek, Tianjiao Wang, Jun Huang. RegCAR-TTM: Enabling next-generation CAR-T therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3579.