A chimeric GM-CSF/IL18 receptor to sustain CAR T-cell function

Abstract

The inability of CAR T-cells to sustain their effector function after repeat exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T-cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T-cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T-cells had a significant greater ability to expand and produce cytokines in comparison to their unmodified counterparts targeting EphA2 or HER2. In vivo, CAR.GM18 T-cells induced tumor regression at cell doses at which standard CAR T-cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T-cells to bolster their antitumor activity.