Engineering CAR T cells with a GM-CSF:IL-18 cytokine switch receptor results in potent antitumor activity in solid tumors

Abstract

Abstract Immunotherapy in the form of chimeric antigen receptor (CAR) T cells has emerged as a promising treatment option for various cancers following its success for the treatment of B cell hematological malignancies. However, the solid tumor microenvironment (TME) has presented many challenges to CAR T cell efficacy and persistence, in part due to lack of T cell-supportive cytokines at the tumor site. We hypothesized that we could improve the efficacy of CAR T cell infusion by engineering a self-sustaining cytokine receptor that would fuel CAR T cells in the TME. One cytokine that is abundantly produced by CAR T cells upon stimulation and is abundant in the TME is the myeloid cytokine GM-CSF. We exploited this biology to design a chimeric cytokine switch receptor that would bind GM-CSF, but signal intracellularly through the IL-18 receptor (GM18). This switch receptor encoded by a retroviral vector was transduced into second generation CAR T cells targeting different solid tumor antigens in order to test the effect of GM18 in multiple model systems. In culture, GM18-expressing CAR T cells initially killed tumor cells to the same degree as unmodified CAR T cells, but displayed greater expansion when repeatedly challenged with tumor cells over time. In vivo, GM18+ CAR T cells exhibited enhanced antitumor activity compared to unmodified CAR T cells in NSG experimental models of solid tumors. These findings paralleled greater expansion and persistence by GM18+ CAR T cells, leading to improved survival. Overall, this work demonstrates the GM18 cytokine switch receptor as an advantageous modification to CAR T cells in solid tumors, suggesting this receptor could be a novel mechanism to modify existing cellular therapies to enhance efficacy in solid tumors.