Program Summary Although allogeneic hematopoietic cell transplantation (HCT) provides curative therapy for many patients with hematologic malignancies, disease relapse and chronic graft versus-host-disease (GVHD) continue to be major impediments to success. Both of these obstacles represent failures of immune regulation. Inadequate recognition and destruction of residual tumor cells by a newly engrafted donor immune system permit recurrence of a patient’s malignancy, while uncontrolled reactions against host antigens lead to GVHD. Enhancing immune responses directed against residual leukemia cells while controlling responses directed against normal host tissues is critical to improving patient outcomes after allo-HCT. The overall goal of this Program is to gain deeper insight into donor and host factors that contribute to these failures and to design and implement innovative immunologic approaches to correct them. This goal will be accomplished through clinical and laboratory studies carried out in 3 Projects and supported by 3 Shared Resources. The projects and cores are highly interactive and led by investigators who have collaborated in a series of studies leading to the development of provocative clinical trials to evaluate new strategies for preventing relapse in high risk transplant recipients, treating relapse in patients post-transplant, and tackling refractory chronic GVHD. Prevention trials include include checkpoint inhibition with ipilumumab, engineered whole cell vaccination, and development of personalized neoantigen/minor histocompatibility antigen vaccines. Treatment trials include combinatorial strategies pairing checkpoint inhibitors with engineered cellular therapy to treat patients who have relapsed post-HCT. Trials in chronic GVHD will test development of synergies between Treg expansion and B cell modulation. Dissection of the evolution of both leukemia cells and surrounding immune cells will inform our understanding of tumor evasion mechanisms and how they might be overcome. To this end, the Program sets out to define predictors and mechanisms of response or resistance of AML/MDS, to determine the changes in the composition and functional state of marrow-infiltrating immune cells, and to track evolving antigen-T cell interactions in association with response to post-transplant immunomodulation. Additionally, further understanding how donor derived clonal hematopoiesis shapes hematopoietic and immunologic reconstitution to influence clinical outcomes will create new interactions that may be amenable to future interventions leading to the development of novel therapeutic strategies. Taken together these efforts will give critical insights into understanding mechanisms of immune dysregulation and how they lead to relapse and chronic GVHD post-HCT as well as creating novel interventions address these obstacles to cure.