Checkpoint inhibition to prevent or treat relapse in allogeneic hematopoietic cell transplantation

In the past decades, survival has improved after allogeneic hematopoietic cell transplantation (allo-HCT) due largely to advances in the prevention of graft-vs.-host disease (GVHD) and opportunistic infection. However, few inroads have been made into the problem of leukemia relapse which is the primary reason for failure of allo-HCT. The graft-vs.-leukemia (GVL) response, in which engrafted immunocompetent donor immune cells can eliminate leukemia cells, is acknowledged as the foundation upon which the curative potential of allo-HCT is based. Despite our strongly held faith in its existence, we remain unable to define GVL on a mechanistic level. T cells, in part, mediate GVL though the roles of specific T cell subsets, NK cells, B cells, macrophages remain elusive. A higher frequency of marrow-infiltrating T cells expressing PD-1, CTLA-4, and TIM-3 and other immune checkpoints have been observed in relapsed patients compared to those in remission. Studies have described the association of T cells expressing an exhausted phenotype with response to immune manipulation post-HCT. In light of these observations and the well documented activity of immune checkpoint blockade (CPB) in transplant naïve patients with hematologic malignancies, considerable interest has developed in evaluating strategies incorporating CPB to address relapse post-HCT. While checkpoint inhibitors may be provocative agents to test, they also raise concern for potential induction of GVHD and uncontrollable immune breakthrough events. This review will lay the framework upon which CPB is being utilized post-HCT, describe early clinical results, and lay out future directions.