The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

Abstract

The online version of this article has a Supplementary Appendix. BackgroundWe have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and MethodsWe evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. ResultsThe combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. ConclusionsThe current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.Key words: allogeneic transplant, sirolimus, bortezomib, graft-versus-host, graft-versusleukemia. Haematologica 2012;97(9):1329-1337. doi:10.3324/haematol.2011 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n Citation: Caballero-Velázquez T, Sánchez-Abarca LI, Gutierrez-Cosio S, Blanco B, Calderon C, Herrero C, Carrancio S, Serrano C, del Cañizo C, San Miguel JF, and Pérez-Simón JA. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graftversus-leukemia effect after allogeneic transplantation. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

Sirolimus and post transplant Cy synergistically maintain mixed chimerism in a mismatched murine model

“…Other groups have suggested bortezomib as a synergistic alternative in combination with sirolimus, but these studies also rely upon infusion of previously tolerized splenic lymphocytes. 42 Our data suggest that inhibiting T-cell responses with CSA does not allow mixed chimerism induction, while blocking mTOR promotes stable mixed chimerism without additional lymphocyte infusions.…”

New perspectives on the use of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation and graft‐versus‐host disease

“…However, bortezomib has also been proposed as a potential combination partner for sirolimus in a preclinical study also showing a maintained graft vs . leukaemia (GVL) effect .…”

Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…Similar effects on T cells were described for the combination of bortezomib and sirolimus. These effects were synergistic because of the inhibition of the phosphorylation of pAKt and pErk pathways, typically not inhibited by bortezomib alone [11].…”

“…Effects of bortezomib on T cells T cells exposed to bortezomib exhibit complete occupancy of all constitutive and immune proteasomal proteolytic units. This results in the rapid accumulation of polyubiquitinated proteins, including several regulatory proteins involved in cell signaling and survival pathways [9][10][11]. Consequently, the effects of bortezomib on T cells span their activation, function, proliferation, and viability.…”