GVHDの病態生理と白血病再発メカニズムに基づくGVHD・GVLの分離を目指す新戦略

Graft-versus-host disease

The Japanese Society of Hematology

Rinsho Ketsueki

Allogeneic hematopoietic cell transplantation (allo-HCT) offers curative potential for acute myeloid leukemia (AML) through its graft-versus-leukemia (GVL) effects, but this same alloreactivity can cause graft-versus-host disease (GVHD), making separation of these effects a central challenge. Proposed mechanisms of post-allo-HCT immune evasion by AML cells include HLA loss via 6p loss of heterozygosity, epigenetic HLA class II silencing, upregulation of immune-suppressive ligands on AML cells, and persistence of leukemia stem cells (LSCs) after transplantation. In addition, donor T-cell exhaustion and an immunosuppressive tumor microenvironment may contribute to post-transplant relapse. We summarize emerging strategies to ameliorate GVHD without attenuating GVL, including intensified local therapy, selective trafficking blockade, S1PR modulators that limit pathogenic T-cell migration, and tissue-protective agents that enhance epithelial regeneration and prevent the establishment of inflammatory memory. We also outline maintenance approaches designed to restore leukemia immunogenicity without exacerbating GVHD, including inhibition of MDM2, EZH2, menin, and FLT3-ITD; IFN-α-based immune modulation; hypomethylating agents; and minor histocompatibility antigen-directed vaccines intended to selectively elicit anti-leukemia alloresponses. Finally, optimization of calcineurin inhibitor timing in post-transplant cyclophosphamide-based allo-HCT may help balance GVHD prevention and GVL preservation. Collectively, these growing mechanistic and clinical insights are making functional separation of GVL from GVHD increasingly feasible.