Myeloid Leukemias represent a growing problem in our aging population. Although treatment of these leukemias has advanced considerably over the past couple of decades, most of these myeloid leukemias still have poor prognosis, particularly in the elderly, and require hematopoietic cell transplants to fully kill the tumor, which is both costly and risky. A great deal of excitement has recently been placed on cellular therapies to treat tumors. Natural Killer NK cell immunotherapies could be used to treat myeloid tumors, but these cells require help in being targeted to the tumor and overcoming inhibitory signals that help the tumor escape recognition and killing. Our group has recently described small bivalent molecules termed BiKEs that target NK cells to myeloid tumors and induce NK cell mediated tumor killing. Though these molecules show promise, the work scope proposed here builds on them through incorporation of signals that will maximize NK cell function. This will be achieved by creating trivalent molecules termed TriKEs that target and activate NK cells but also either block inhibitory signals provided by the tumor cells, further enhance the activating signals provided by the BiKE, or drive expansion and maintenance of the NK cells killing the tumor cells.