Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine

Allogeneic bone marrow transplantation (BMT) can be accompanied by a benefi cial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity, However, BRIT donor T cells are not exposed to target antig ens of GVT activity until transfer to the host, where tumor antigen present ation may be suboptimal, This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derive d tumor cell vaccine would substantially increase GVT activity and extend s urvival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarc oma or leukemia, and they were used as BRIT donors. Recipients were H-2-mat ched, minor histocompatibility antigen-mismatched C57BL/6 mice with previou sly established micrometastatic tumors. Donor immunization led to a signifi cant increase in GVT activity that was T cell dependent and cell dose depen dent. In some settings, donor immunization also prolonged survival of recip ients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease su ch that long-term survival was uncommon. In vitro cytotoxicity assays indic ated that donor immunization induced both tumor-selective and alloreactive cytolytic T-cell populations. In vivo cross-protection assays showed that a substantial portion of the GVT effect was mediated by alloreactive cells n ot specific for the immunizing tumor. In conclusion, immunization of alloge neic BMT donors with a recipient-derived whole tumor cell vaccine substanti ally increases GVT activity but also exacerbates graft-versus-host disease.