Novel approaches for separating graft-versus-leukemia effects from graft-versus-host disease

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for various hematologic malignancies. Separation of graft-versus-leukemia (GVL) effects from graft-versus-host disease (GVHD) remains one of the central challenges in allo-HCT. However, relapse after allo-HCT remains associated with poor prognosis, and effective strategies that preserve graft-versus-leukemia (GVL) effects while preventing graft-versus-host disease (GVHD) are still lacking. Recent advances have revealed that post-transplant relapse is driven by diverse mechanisms, including leukemia-intrinsic immune escape, donor T-cell exhaustion, and persistence of leukemia stem cells. Emerging therapeutic strategies, such as selective modulation of T-cell trafficking and enhancement of tissue tolerance, are promising approaches to ameliorate GVHD without attenuating GVL effects. Additional approaches including cellular therapies, selective immune modulation, and restoration of leukemia immunogenicity are also being actively explored. Furthermore, restoration of leukemia immunogenicity and targeted elimination of leukemia stem cells are expected to provide new opportunities to prevent relapse without aggravating GVHD. In addition, approaches that reshape the tumor immune microenvironment or modulate T-cell exhaustion may further strengthen GVL activity while limiting harmful alloreactivity. These developments suggest that the long-considered difficult goal of separating GVHD from GVL effects may become achievable in the near future. In this review, we provide an overview of novel therapeutic targets aimed at achieving the separation of GVHD and GVL, with a particular focus on findings related to acute myeloid leukemia.