Synthetic gene expression regulator switches (SynGERS) expressed in CAR T cells to cure children with solid tumors
The immune system can recognize and eliminate cancer. Genetically engineering a unique type of immune cells called T cells can result in upto 90% complete elimination of leukemia cells, a type of blood cancer. Such strategy holds exceptional promise for children with solid tumors. However, additional genetic engineering modifications are required to overcome the solid tumor microenvironment which can stop the engineered T cells. We developed a novel system called “Synthetic Gene Expression Regulator Switches” – SynGERS. When engaging cancer cells SynGERS executes miniprograms in tumor specific T cells. SynGERS expressing T cells can increase the expression of genes related to survival while suppressing those associated with T cell dysfunction simultaneously. There are several genes that can promote T cells’ ability to survive and expand; and similarly, there are several genes that can block their antitumor function. These master regulator genes can be manipulated individually and have been shown to enhance the antitumor activity of engineered T cells. It is unknown which master regulator induces the most potent antitumor effect; furthermore, it is unclear what are the most effective combinations. To address this knowledge gap, our proposal will systematically evaluate a library of SynGERS built to modulate the expression of master regulators of T cell function in a tumor specific manner.
Project Goals:
We have developed a library of SynGERS which can modulate master regulators of T cell function including increasing the expression of those that help and repressing the expression of genes that inhibit tumor redirected T cells. Importantly, SynGERS encoding miniprograms are executed in a tumor antigen dependent manner. Our first goal is to determine which SynGERS enhance the expansion and persistence of tumor redirected T cells the most. This is important as expansion and persistence is associated with improved survival of patients with leukemia treated with tumor redirected T cells. Our second goal is to identify the SynGERS inducing the most potent antitumor activity of T cells and understand how this new, artificial gene expression miniprogram works to rewiring tumor redirected T cells. Our long-term goal is to evaluate this SynGERS expressed in tumor redirected T cells in children with solid tumors.
