Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function
Benjamin Salzer, Christina M. Schueller, Charlotte U. Zajc, Timo Peters, Michael A. Schoeber, Boris Kovačic, Michelle C. Buri, Elisabeth Lobner, Omer Dushek, Johannes B. Huppa, Christian Obinger, Eva Maria Putz, Wolfgang Holter, Michael W. Traxlmayr, Manfred Lehner
Abstract
T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.