In vitro assessment of an engineered tBID-based safety switch system in human T lymphocytes

Abstract

Cell therapy as a promising therapeutic modality to treat cancer has been intensively studied for decades. However, the clinical trials have indicated that patients under T cell therapy may develop severe cytokine release syndrome resulting in hospitalization or even death. Furthermore, genetic modifications to promote proliferation and persistence of T cells could result in high numbers of long-lived engineered cells in patients after treatment. In this study we developed a novel tBID-based safety switch regulated through a small molecule inducible on switch to control undesired toxicity or ablate engineered cells as needed. We compared several tBID-based safety switch constructs with the clinically validated safety switches, HSV-TK (human herpes simplex virus thymidine kinase) and iCasp9 (inducible Caspase 9), few tBID-based safety switch constructs were systematically tested and investigated in vitro in Jurkat or human primary T cells. We demonstrated that our novel tBID based safety switch, with optimization, was able to eliminate up to ~90% of transduced human primary T cells within 72hr after activation, providing an alternative switch system to manage safety concerns for cell therapy.