Dr. Felices, the PI in this proposal, is a trained immunologist with expertise on signal transduction in his first year as an assistant professor at the University of Minnesota. He obtained his training in academia (UMASS and UMN) and industry (Novartis) focusing in signal transduction in the immune system and tumorogenesis. As Jr. Faculty, Dr. Felices research is aimed at maximizing the immunotherapeutic value of natural killer (NK) cells against myeloid leukemias, like CML, AML and MDS, covered by Myeloproliferative disorders FY15 topic area. He proposes to do this by incorporating his signaling knowledge into a novel platform of molecules, termed bi- or Tri-specific killer engagers (BiKEs and TriKEs). Our group has shown that BiKEs target NK cells to myeloid leukemic cells through generation of an immune synapse between CD33, on the myeloid leukemic cell, and CD16,on the NK cell. Dr. Felices proposal aims to carry these molecules into the next generation and given the outstanding translational environment surrounding him at the University of Minnesota, he is uniquely positioned to move these molecules into the clinic and advance the current immunotherapeutic efforts against myeloid leukemias. His mentor, Dr. Jeffrey S. Miller, is a world-renowned NK cell immunotherapy expert with vast experience in clinical approaches targeting myeloid leukemias using NK cells. He is well published and funded in this area and has a proven track record in mentoring. Besides his leadership role at the University of Minnesota and access to a well-populated bank of myeloid leukemia clinical samples, generated from several clinical trials led by him and his colleagues, Dr. Millers group pioneered the NK BiKE and TriKE work making him the ideal mentor for this proposal.