The five year survival for high risk patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) is less than 10% and 30% respectively warranting development of novel therapeutic approaches. Most patients achieve remission with chemotherapy, but many relapse because of minimal residual disease (MRD) containing leukemic stem cells (LSCs). AML LSCs express a cell surface marker called CD123 while ALL LSCs express a marker called CD19. During the tenure of our CIHR support we have developed a method to combine cellular immunotherapy using a gene modified natural killer cell line (CD16+NK-92) with antibodies that can target CD123 and lead to prolonged survival of immunodeficient mice bearing human AML. This important synergistic finding has prompted us to propose testing a variety of antibodies and doses to improve this survival benefit. Using the same method we also have outlined a strategy to develop a therapy for ALL by using anti-CD19 antibodies combined with the CD16+NK-92 cells. Given the recent success of gene modified T-cell therapy for leukemia in curing some refractory ALL patients published in the New England Journal of Medicine, we wish to attempt a similar approach for AML. This would be done by genetic modification of the parent NK-92 cell line to express a chimeric antigen receptor (CAR) able to recognize the CD123 antigen. This novel biologic therapeutic agent would be tested in a mouse model of human leukemia and compared to our other approach using CD16+NK-92 cells and antibody therapy. These preclinical animal studies if promising would inform the development of a clinical protocol.