Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent...

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. We also determined the effects of ixazomib in a murine GvHD model. Although ixazomib suppressed naïve human DC maturation, it had only a limited effect on cell viability. Ixazomib decreased pro-inflammatory cytokine production of resting DCs. This effect was diminished or reversed when DCs were pre-stimulated. In vivo, ixazomib administered post-transplantation on days +1 and +4 or days -1, +2, and +5 ameliorated GvHD in comparison to the GvHD group. Although a fraction of mice treated according to the prolonged schedule died abruptly after the day +5 treatment, both schedules resulted in improved overall survival. When we examined the effects of ixazomib on splenic cells and serum cytokines, we found that ixazomib exerted complex schedule-dependent immunomodulatory effects. Our study provides a rationale for the potential use of ixazomib in the prevention of GvHD.