Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib
Kai Sun, Lisbeth A Welniak, Angela Panoskaltsis-Mortari, Matthew J O'Shaughnessy, Haiyan Liu, Isabel Barao, William Riordan, Raquel Sitcheran, Christian Wysocki, Jonathan S Serody, Bruce R Blazar, Thomas J Sayers, William J Murphy, Kai Sun, Lisbeth A Welniak, Angela Panoskaltsis-Mortari, Matthew J O'Shaughnessy, Haiyan Liu, Isabel Barao, William Riordan, Raquel Sitcheran, Christian Wysocki, Jonathan S Serody, Bruce R Blazar, Thomas J Sayers, William J Murphy
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.
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Source: PubMed