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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.; Vitetta, Ellen S.
Proceedings of the National Academy of Sciences - PNAS, 05/2004, Volume: 101, Issue: 21Journal Article
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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