Kate Amato Foundation Awarded Projects

Project Description:

High-risk neuroblastoma is a pediatric cancer of the nervous system that often presents at an advanced stage and with genetic mutations that portend poor prognosis. Our studies using an animal model of high-risk neuroblastoma demonstrate that certain white blood cells called invariant natural killer T (iNKT) cells are present within the tumors at unexpectedly elevated frequencies – much higher than the frequencies of conventional T cells (white blood cells that are believed to be very important for killing cancer cells). This finding prompted us to theorize that iNKT cells may not only be better at trafficking to, and persisting inside of neuroblastoma tumors, but that if we were to activate them inside the tumors, that they may provide a novel and effective mode of therapy. Consistent with this theory, prior analyses of human neuroblastomas showed that children whose tumors contain higher frequencies of iNKT cells have an almost double 5-year survival rate compared to those with tumors with low iNKT cell frequencies. To better understand the features that allow iNKT cells to survive and function in neuroblastoma tumors, we will use our animal models to define how iNKT cells generate energy, and how this process is influenced by the tumor microenvironment. Next, we will probe the therapeutic efficacy of a novel reagent developed by us that uniquely targets iNKT cells against cancer cells. Using this reagent, we will determine whether activating intratumoral iNKT cells and directing their killing against neuroblastoma results in cancer control. We believe our proposed studies will improve our understanding of iNKT cell biology and antitumor function and will aid the development of combinational immunotherapy for high-risk neuroblastoma. We believe that our group’s expertise and that of the Center for Childhood Cancer Research (CCCR; a well-recognized leader in neuroblastoma research) uniquely positions this proposal for success and immediate translational impact.