Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.
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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.
Sun, K., Welniak, L. A., Panoskaltsis-Mortari, A., O'Shaughnessy, M. J., Liu, H., Barao, I., ... Murphy, W. J.
complete list of authors
Sun, Kai||Welniak, Lisbeth A||Panoskaltsis-Mortari, Angela||O'Shaughnessy, Matthew J||Liu, Haiyan||Barao, Isabel||Riordan, William||Sitcheran, Raquel||Wysocki, Christian||Serody, Jonathan S||Blazar, Bruce R||Sayers, Thomas J||Murphy, William J