Abstract 2751: The modular Tmod dual_receptor system exploits tumor deletions to achieve robust tumor-selective cytotoxicity

Abstract

We set out to examine the behavior in preclinical models of a dual-receptor cell therapy approach (Tmod࣪ system) designed to exploit instances of somatic LOH in cancer that can be readily identified through molecular diagnostics. We utilized quantitative pharmacologic assays in vitro and dual-flank efficacy/selectivity models in vivo to test the activity of a variety of constructs comprised of: (i) CAR “activators” that target tumor-associated antigens (TAAs) such as CEA, MSLN and others; and, (ii) LIR-1-based “blockers” that target HLA class I proteins. We generated substantial datasets around multiple targets, including well known tumor-associated antigens (TAAs). In the presence of the HLA class I blocker antigen, Tmod cells were OFF within a wide range of activator antigen expression levels on the “normal” target cells. They were ON when tumor cells expressed the TAA without the HLA blocker antigen, and killed tumor cells selectively even in mixed tumor-normal cell populations. The Tmod system transformed imperfect TAAs into true tumor-selective targets, where the activity of the engineered T cells is controlled by the presence/absence of the HLA blocker antigen. The system was sufficiently modular to use with autologous and allogeneic products. Several of these Tmod constructs are advancing to the clinic where a robust genetic selection tool is being used to screen patients for treatment and match them with a suitable Tmod therapy. In summary, Tmod is a robust system with quantitative pharmacologic behavior in preclinical models consistent with efficacy and safety across a range of targets. Citation Format: Han Xu, Agnes Hamburger, Yuta Ando, Grace Asuelime, Kristian Bolanos, Mark Daris, Breanna DiAndreth, Maria C. Imun, Wen-Hua Lee, Chuck Z. Li, Breanna Luna, Diane Manry, Aaron D. Martin, Michele E. McElvain, Jee-Young Mock, Martin Naradikian, Mark L. Sandberg, Julyun Oh, Sanam Shafaattalab, Shruti Sharma, Talar Tokatlian, Xueyin Wang, Lu Min Wong, Alexander Kamb. The modular Tmod dual_receptor system exploits tumor deletions to achieve robust tumor-selective cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2751.