Synthetic Gene Expression Regulatory Switches (SynGERS) for Improved CAR T Cell Function in Pediatric Solid Tumors
Immunotherapy using genetically engineered special white blood cells has revolutionized the treatment of children and adults with blood cancers including leukemias and lymphomas. The strategy has great potential to cure children with solid cancers; however, these tumors use mechanisms to inhibit the engineered white blood cells. When engineered cells lose their functionality in solid tumors, their program changes in response to the cancer cells. In this application, we will introduce mini programs into tumor-redirected white blood cells with the goal of overcoming solid tumors. To achieve this objective, we have designed "Synthetic Gene Expression Regulatory Switches" which will be turned ON only when needed and help the white blood cells grow, last long and eliminate tumors. Importantly, we have designed a library containing these mini programs and will select the best one for further development in the clinical setting to help children with solid tumors.
Project Goal:
Our strategy has two interrelated goals: 1) we will determine which mini programs induce the best white blood cell growth and persistence in preclinical tumor models. This is very important as in patients with leukemia, the ability of engineered white blood cells to grow and last, is associated strongly with antitumor activity. 2) we will identify the mini program that helps the special white blood cells to eliminate the solid tumors in the petri dish and in tumor-bearing mice. Lastly, we will also characterize how such reprogramming changes the innate operating program of the white blood cells.
