We hypothesize that exploitation of NK cell function by immunogenetic influences, activation with IL-15/IL- 15R?-Fc complexes and targeting through CD16 can overcome inhibitory KIR interactions with HLA that prevent target cell killing. NK cell activation in vivo can augment the successes of cancer suppression, and in a series of clinical trials we will test the translational success of our findings. SA1 will include continuation of our prospective multicenter KIR donor genotyping trial to identify the optimal KIR genotyped donor for unrelated donor transplantation for AML. Having shown feasibility in enrolling the first ~400 recipients and their potential donors, we will continue to prospectively identify donors with favorable KIR B haplotype that we demonstrated can reduce risks of relapse and improve disease-free survival. The importance of CMV reactivation in modifying this NK-mediated favorable outcome will be explored. SA2 will study how enhancing NK cell activity using IL-15/IL-15R?-Fc complexes can enhance the success of NK cell adoptive transfer in the pre-transplant preparative regimen followed by a novel TCR?/?-depleted graft to accelerate lymphoid reconstitution after transplantation. Post-transplant IL-15/IL-15R?-Fc complexes infusions will augment NK cell proliferation followed by a randomized trial testing adoptive NK cell transfer versus endogenous NK activation without donor NK infusion; all to control high-risk leukemia after haploidentical transplantation. SA3 will target myeloid hematologic malignancies with bispecific killer engagers (BiKEs), our newly developed myeloid-specific CD16x33 single-chain Fv constructs. These direct activated NK cells to kill myeloid tumors and myeloid- derived suppressor cells to control advanced myeloid malignancies. Overall, using discoveries derived from Projects 1 and 2, we will translate knowledge about the immunogenetic regulation if NK cell function and discoveries about CMV-induced adaptive NK cells with our novel pharmacologic agents to test these approaches to treat cancer. We will monitor the immunologic and clinical consequences and translate our findings into coordinated and complementary basic and clinical research to exploit NK cell control of advanced cancer.