Exploiting Hypoxia for T-Cell Immunotherapy in Neuroblastoma

My career goal is to become an independent investigator that performs translational research to study T cell immunotherapy against solid tumor such as neuroblastoma (NB). NB is the most common solid tumor of childhood and current therapies against NB is not very effective. Genetically altered cells from the patient's own immune system called CAR-T cells can be used to treat lymphoid leukemia, but they are less effective against NB. I think that one of the reasons for this reduced activity in NB is the tumor defense mechanism against our immune system. Understanding how this defense system of tumor is pivotal in improving the efficacy of our CAR-T cells to eliminate tumor cells. Thus, I believe the Horizon Award is a unique opportunity to start my research in this area with the ultimate goal to provide additional treatment option to NB patients refractory to standard chemo/radiotherapy. One of defense mechanisms in solid tumor such as NB is the low concentration of the oxygen, also known as hypoxia, in the locations where the NB cells grow. T cells use oxygen and if the oxygen is low when they encounter the tumor cells of NB, the function of T cells is dramatically reduced. Thus, I will study if CART cells targeting NB can work in hypoxia. Based on my preliminary studies, I think that a specific population of CAR-T cells is able to survive and function when the concentration of the oxygen is low. I am then planning to understand which mechanisms these cells are using to survive in hypoxia and adapt these mechanisms to all the other populations of CAR-T cells so that they will all be armed to function against NB tumor cells in hypoxia. Moreover, I proposed a novel strategy to improve the safety of CAR-T cells without hampering their efficacy by taking advantage of an intrinsic cellular process to take up glucose, which is the main nutrient for CAR-T cells. Since I have extensive experience with the preclinical models and my mentor, Dr. Dotti, has a strong background in clinical studies of NB, I am confident my research can be translated into the clinic within 5 years. Since our project aims to improve the efficacy and safety of current treatment for NB, a common childhood cancer, it will alleviate the mental and physical burden for active duty Service members and their children who suffer from this disease.