Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib

Abstract

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

“…In conclusion, the present study suggests a novel mechanism of immunomodulation by proteasome inhibitors which may account, at least in part, for the immunosuppressive effects observed in the animal models [20][21][22][23][24][25][46][47][48][49]. Finally, the observation of DC and lymphocyte susceptibility to bortezomib fosters the evaluation of this compound in clinical settings where antitumor activity and modulation of immunity are both desired, such as allogeneic bone marrow transplantation/graft-versus-host disease or autoimmunity associated with leukemias or lymphomas.…”

“…In the animal model, proteasome inhibitors were reported to have immunosuppressive properties as shown by prevention of allograft rejection and graft-versus-host disease and by their efficacy in the treatment of autoimmune disorders, including experimental autoimmune encephalomyelitis, psoriasis, and possibly type I diabetes [20][21][22][23][24][25]. Heavy patients' pretreatment and/or pre-existing diseaserelated immunodepression hamper the evaluation of the immune effects of proteasome inhibitors in humans.…”

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…Bortezomib may also have immunosuppressive effects, which could account for some of the activity of this combination in vivo. Bortezomib has been shown to inhibit plasma cells, dendritic cells and the generation of graft-versus-host disease (Sun et al, 2004;Nencioni et al, 2006;Neubert et al, 2008). However, the Reolysin/bortezomib combination displayed potent efficacy in both a human xenograft model in SCID mice and a syngeneic model in immunocompetent mice, suggesting that the therapeutic effects of this combination involves direct tumor cytotoxicity, rather than complete dependence upon an immune response.…”

NF-κB and the regulation of hematopoiesis

“…PS-341, a proteasome inhibitor known to inhibit NF-kB activation, protected mice from GVHD. 89 Very interestingly, graft versus tumor responses were not abolished after systemic PS-341 treatment of mice with advance tumors. More recently, PS-1145, an IKK inhibitor, has been shown to be protective against GVHD.…”