Abstract 2546: Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors

Abstract

Abstract Chimeric antigen receptor modified T cell (CAR-T) therapy has revolutionized personalized cancer treatment. The recent FDA approval of two CAR-T therapies for hematological cancers has marked a pivotal milestone in this new era of cellular therapies. CAR-T cells are genetically modified to become activated and proliferate in the presence of tumor antigens. In patients with high tumor burden and rapid T cell expansion, however, severe side effects including severe cytokine release syndrome (sCRS) and life-threatening cerebral edema may occur. To “fine-tune” CAR-T cell activity in real time, we devised a three-pronged therapeutic strategy by using (1) 4-1BB-CD3ζ CARs expressing anti-fluorescein (anti-FITC) scFv instead of an anti-tumor ligand/self-antigen scFv, (2) low-molecular-weight bi-specific adaptors comprised of a FITC hapten linked to a tumor-specific ligand, and (3) competitors that can interfere with the adaptor/CAR-T interaction with tumor cells. Using folate-FITC (EC17) as the bi-specific adaptor molecule, we evaluated the performance of FITC-CAR-T cells in various folate receptor (FR)-positive tumor models. Our results show that CAR-T activation and proliferation in-vivo was EC17- and tumor FR-dependent. Treatment-related toxicity (sCRS) was observed but could be easily controlled, or even prevented, by adjusting the concentration, dosing frequency or timing of bi-specific adaptor administration. Importantly, animals experiencing sCRS could be rescued by administrating competitors of the bi-specific adaptor. In the case of EC17/CAR-T therapy, improved animal behavior was observed as early as a few hours after dosing with a rescue agent and a rapid reduction of interferon-γ was also detected. Circulating CAR-T cells remained functional, and could be re-activated following subsequent EC17 doses. Taken together, our bi-specific adaptor/CAR-T approach offers a unique combination of a man-made hapten (FITC), flexible dosing control, and sCRS prevention/rescue without compromising antitumor activity or permanently removing CAR-T cells. Further studies are warranted to provide a rational basis for translating such therapeutic practice to the clinic. Footnotes HC and JL contributed equally to this work. Citation Format: Haiyan Chu, Yingjuan Lu, Yong Gu Lee, Leroy Wheeler, Mellissa Nelson, Elaine Westrick, Marilynn Vetzel, Patrick J. Klein, Philip S. Low, Christopher P. Leamon. Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors [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 2546.