Project 4: Epigenetic modulation of graft versus host disease and graft versus leukemia
Three-dimensional structure showing binding of the DNA methyltranferase 1 (DNMT1) inhibitor, RG-108, to the parent enzyme. Our data suggest that inhibition of DNMT1 leads to the production of regulatory T cells, which, in turn, reduce graft-versus-host disease.
Allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplastic syndromes (MDS) and aplastic anemia.
The therapeutic benefits of allo-HSCT for hematologic malignancies are primarily derived from an anti-leukemia effect (graft-versus-leukemia effect or GvL) that is mediated by mature donor T cells present in the donor graft. Unfortunately, the same donor T cells that mediate the beneficial GvL effect can also cause graft-versus-host disease (GvHD), the major life-threatening complication of allo-HSCT. Those patients that develop acute GvHD after transplant have an increased risk of treatment related mortality. Thus, defining an approach to harness the GvL effect while reducing or eliminating GvHD should have a transformative impact on enhancing the quality of life and survival of transplant patients.
The overall objective of this application, is to assess the efficacy of azacitidine (AzaC) to suppress GvHD while maintaining GvL in humans. Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and mitigate GvHD, while preserving the beneficial GvL effect. It has been shown that the expression of Foxp3, the master gene of Tregs, is regulated by DNA methylation. We recently reported that the hypomethylating agent azacitidine (AzaC) induces FOXP3 expression in vitro and increases Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allo-HSCT model.
Our central hypothesis is that AzaC will induce similar immunomodulatory effects (induction of FOXP3+ Tregs, suppression of GvHD and preservation of GvL activity) in human T cells that will reduce GvHD and preserve GvL. In Aim 1 we will perform a Phase I/II clinical trial to examine the safety and effectiveness of AzaC treatment as GvHD prophylaxis in patients with AML and MDS undergoing allogeneic stem cell transplant. In Aim 2 we will interrogate the molecular mechanism/s underlying the suppressive function of AzaC-induced Tregs and optimize the use of AzaC and and other DNMT1 inhibitors to modulate GvHD and GvL in murine allo-HSCT models.