Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic strategy for patients with both malignant and nonmalignant disorders. The therapeutic benefits of allo-HSCT in malignant disorders are primarily derived from the graft-versus-leukemia (GvL) effect, in which T cells in the donor graft recognize and eradicate residual malignant cells. However, the same donor T cells can also recognize normal host tissues as foreign, leading to the development of graft-versus-host disease (GvHD), which is difficult to separate from GvL and is the most frequent and serious complication following allo-HSCT. Inhibition of donor T cell toxicity helps in reducing GvHD but also restricts GvL activity. Therefore, developing a novel therapeutic strategy that selectively suppresses GvHD without affecting GvL is essential. Recent studies have shown that inhibition of histone deacetylases (HDACs) not only inhibits the growth of tumor cells but also regulates the cytotoxic activity of T cells. Here, we compile the known therapeutic potential of HDAC inhibitors in preventing several stages of GvHD pathogenesis. Furthermore, we will also review the current clinical features of HDAC inhibitors in preventing and treating GvHD as well as maintaining GvL.

Prevalence and Risk Factors Associated With Corneal Perforation in Chronic Ocular Graft-Versus-Host-Disease

“…1 Graftversus-host disease (GVHD) is a major complication of HSCT and arises when donor-derived T cells recognize recipient antigens as foreign and mount an immune response against recipient tissue. 2,3 The reported incidence of GVHD varies widely from 10% to 90% of patients receiving allogeneic HSCT, and the primary targets of the immunologic response are the skin, gastrointestinal system, liver, lung, oral mucosa, and eyes. [4][5][6] Ocular involvement is seen in 60% to 90% of patients with GVHD, and most of these patients present with chronic ocular GVHD (oGVHD).…”

Epigenetic‐based therapy in allogenic hematopoietic stem cell transplantation: Novel opportunities for personalized treatment

“…[40][41][42][43] Phase 1 and 2 trials have provided preliminary results about the possible beneficial effects of using 5-aza and specific DNMTi and HDACi before and after allo-HSCT in reducing the onset and severity of GVHD. 44 A phase 3 randomized trial evaluating 5-aza in posttransplant patients in complete remission did not show significant results. 45 To enhance their putative therapeutic effects, the prevalent approach in phase 2 trials is the association of these epidrugs with well-established regimens as seen in other types of cancers.…”

The impact of epigenetic modifications on allogeneic hematopoietic stem cell transplantation

“…Histone modifications have been widely targeted in the context of neoplasia and allogeneic HSCT, with several agents inhibiting histone deacetylases now commercially available including but not limited to vorinostat, panobinostat, belinostat, and romidepsin ( 28 , 87 , 88 ). Histone modifications contribute to the regulation of proliferation and cytotoxicity in activated T-cells and histone acetylation was one of the first epigenetic modifications to be studied in preclinical models of acute GVHD ( 87 ).…”