Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib.
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
Kai
K
Department of Microbiology and Immunology, University of Nevada, Reno, NV 89557, USA.
Welniak
Lisbeth A
LA
Panoskaltsis-Mortari
Angela
A
O'Shaughnessy
Matthew J
MJ
Liu
Haiyan
H
Barao
Isabel
I
Riordan
William
W
Sitcheran
Raquel
R
Wysocki
Christian
C
Serody
Jonathan S
JS
Blazar
Bruce R
BR
Sayers
Thomas J
TJ
Murphy
William J
WJ
D000208:Acute Disease / Q000628:therapy; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib