Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans

Abstract

Key Points• HDAC inhibition reduced proinflammatory cytokines and increased regulatory T-cell number and function after allo-HCT.• HDAC inhibition enhanced signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase after allo-HCT.We examined immunological responses in patients receiving histone deacetylase (HDAC) inhibition (vorinostat) for graft-versus-host disease prophylaxis after allogeneic hematopoietic cell transplant. Vorinostat treatment increased histone acetylation in peripheral blood mononuclear cells (PBMCs) from treated patients, confirming target HDAC inhibition. HDAC inhibition reduced proinflammatory cytokine levels in plasma and from PBMCs and decreased ex vivo responses of PBMCs to proinflammatory TLR-4 stimuli, but did not alter the number or response of conventional T cells to nonspecific stimuli. However, the numbers of regulatory T cells (Tregs) were increased, which revealed greater demethylation of the Foxp3 T regulatory-specific demethylation region. Vorinostat-treated patients showed increased expression of CD45RA and CD31 on Tregs, and these Tregs demonstrated greater suppression on a per cell basis. Consistent with preclinical findings, HDAC inhibition also increased signal transducer and activator of transcription 3 acetylation and induced indoleamine-2,3-dioxygenase. Our data demonstrate that HDAC inhibition reduces inflammatory responses of PBMC but enhances Tregs after allo-HCT. (Blood. 2015;125(5):815-819)

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

“…These data (Figure 2A) support in vivo HDAC inhibition by vorinostat. 27 Patients treated with vorinostat also demonstrated lower plasma levels of the cytokine IL-6 (median, 4.2 vs 7.6 pg/mL; P 5 .028) compared with patients who were not treated with vorinostat on day 30 ( Figure 2B), which is consistent with attenuated systemic inflammation. Concentrations of plasma IL-1b, IL-2, IL-8, interferon g, tumor necrosis factor a, soluble IL-2 receptor a, soluble tumor necrosis factor receptor 1, and chemokine (C-X-C motif) ligand 9 were not found to be significantly different between study patients who received vorinostat compared with patients who did not receive vorinostat 30 days after HCT (data not shown).…”

“…Although strategies that mitigate GVHD can result in increased incidence of relapse, we did not observe a rise in relapse, consistent with our previous observations in patients taking vorinostat after matched related donor HCT. 27 We recorded a relapse incidence of 19% (95% CI, 9%-36%) at 1 year in a cohort with predominantly AML/MDS diagnosis (95%), which is commensurate with the 20% to 40% reported in a recent registry study examining AML relapse after URD HCT. 28 Together, the low incidence of relapse and acute GVHD observed in this trial yielded an NRM of 16% (95% CI, 7%-34%) and an overall survival of 76% (95% CI, 63%-92%) at 1 year.…”

“…34 Reduction of IL-6 is consistent with preclinical and clinical data demonstrating that HDAC inhibition can ameliorate inflammation. 15,16,18,27,31,35 Although not measured at a time to allow prediction of acute GVHD onset, the lower soluble ST2 and Reg3a levels in our study cohort likely reflect an attenuated inflammatory response resulting …”

“…No unexpected adverse reactions were observed and were similar to those reported elsewhere, 14 as well as in our previous study. 27 Although limited by the single-arm design, we are encouraged by the low incidence of acute GVHD observed in recipients of myeloablative URD HCT. Jagasia et al recently reported day 100 incidence of grade 2 to 4 acute GVHD of 50% to 60%, after myeloablative, non-TBI-based conditioning URD transplant with bone marrow cells or PBSC and prophylaxis with calcineurin inhibitor (tacrolimus or cyclosporine) plus methotrexate.…”

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…[95] In agreement with preclinical observations, treated patients had low serum levels of inflammatory cytokines, high levels of IDO and high Treg counts. [112] Phase II studies are currently exploring the addition of vorinostat to standard tacro-MTX in the unrelated donor alloHSCT setting (#NCT01789255, #NCT01790568). Importantly, it should be stressed that not all HDAC inhibitors have similar effects on GVHD and, for example, the potent HDAC inhibitor (LBH589, panobinostat) accelerated experimental GVHD.…”