CARTIV - a novel platform for regulation of gene expression under the control of inflammation-induced promoters

Harnessing the immune system to eradicate cancer is becoming a reality in recent years. The ability of immune cells to identify and destruct cancerous cells within the body is showing superior potency; however, such great power also possesses a practical hazard. For example, the usage of engineered immune cells, such as Chimeric-Antigen-Receptor T-cells (CAR-T), is facing the danger of an overt life-threatening immune response. Critically, several patients had already died following adoptive transfer of CAR-T cells. We hypothesize that engineering CAR-T cells to express the activating-receptor within Tumor Microenvironment (TME), but not in normal tissues, will bring a novel safety mechanism. Improved control of the expression of the engineered chimeric receptor is needed to reduce the risks of the life-threatening hazard. This may open the therapeutic window for many tumor-antigens that has low expression on normal cells. We have developed a novel platform for regulation of gene expression under the control of inflammation-induced promoters, together with a Tet-On response circuit. Several promoters were tested in human cells, demonstrating functional abilities to respond to major inflammatory cytokines, and to their combinations, representing TME. Few promotor which showed superior activity were tested in human primary T cells and one was able to activate human primary T cells by controlling the expression of a Herceptin based CAR. This novel platform can improve the various types of CAR-T cells, as well as other engineered immune cells that will provide improved focused activities against their targets within the body.