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 thatprevent target cell killing. NK cell activation in vivo can augment the successes of cancer suppression, and in aseries of clinical trials we will test the translational success of our findings. SA1 will include continuation of ourprospective multicenter KIR donor genotyping trial to identify the optimal KIR genotyped donor for unrelateddonor transplantation for AML. Having shown feasibility in enrolling the first ~400 recipients and their potentialdonors, we will continue to prospectively identify donors with favorable KIR B haplotype that we demonstratedcan reduce risks of relapse and improve disease-free survival. The importance of CMV reactivation inmodifying this NK-mediated favorable outcome will be explored. SA2 will study how enhancing NK cell activityusing IL-15/IL-15R?-Fc complexes can enhance the success of NK cell adoptive transfer in the pre-transplantpreparative regimen followed by a novel TCR?/?-depleted graft to accelerate lymphoid reconstitution aftertransplantation. Post-transplant IL-15/IL-15R?-Fc complexes infusions will augment NK cell proliferationfollowed by a randomized trial testing adoptive NK cell transfer versus endogenous NK activation without donorNK infusion; all to control high-risk leukemia after haploidentical transplantation. SA3 will target myeloidhematologic malignancies with bispecific killer engagers (BiKEs), our newly developed myeloid-specificCD16x33 single-chain Fv constructs. These direct activated NK cells to kill myeloid tumors and myeloid-derivedsuppressor cells to control advanced myeloid malignancies. Overall, using discoveries derived fromProjects 1 and 2, we will translate knowledge about the immunogenetic regulation if NK cell function anddiscoveries about CMV-induced adaptive NK cells with our novel pharmacologic agents to test theseapproaches to treat cancer. We will monitor the immunologic and clinical consequences and translate ourfindings into coordinated and complementary basic and clinical research to exploit NK cell control of advancedcancer.
The goal of this Project is to conduct clinical trials to test novel methods to exploit natural killer (NK) cell activityagainst tumors. We will test a strategy to select unrelated donors for hematopoietic cell transplant (HCT) forpatients with AML based on the genetic profile of their NK cell receptors. We will use the cytokine IL-15 in thesetting of a haploidentical HCT to activate NK cell function. We will test a novel bi-specific killer engager(BiKE) to target NK cells to tumors expressing CD33.
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