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 beneficial T cell-mediated antitumor immune response known as graft-versus-tumor (GVT) activity. However, BMT donor T cells are not exposed to target antigens of GVT activity until transfer to the host, where tumor antigen presentation may be suboptimal. This study tested in a murine model the hypothesis that immunization of MHC-matched allogeneic donors with a recipient-derived tumor cell vaccine would substantially increase GVT activity and extend survival of BMT recipients with preexisting micrometastatic tumor. C3H.SW and C57BL/10 mice were immunized against a C57BL/6-derived fibrosarcoma or leukemia, and they were used as BMT donors. Recipients were H-2-matched, minor histocompatibility antigen-mismatched C57BL/6 mice with previously established micrometastatic tumors. Donor immunization led to a significant increase in GVT activity that was T cell dependent and cell dose dependent. In some settings, donor immunization also prolonged survival of recipients with preexisting micrometastatic tumors. However, donor immunization significantly increased the incidence of fatal graft-versus-host disease such that long-term survival was uncommon. In vitro cytotoxicity assays indicated 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 not specific for the immunizing tumor. In conclusion, immunization of allogeneic BMT donors with a recipient-derived whole tumor cell vaccine substantially increases GVT activity but also exacerbates graft-versus-host disease.
Anderson
L D
LD
Department of Experimental Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Petropoulos
D
D
Everse
L A
LA
Mullen
C A
CA
D000818:Animals; D016026:Bone Marrow Transplantation; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology*; D020350:Graft vs Tumor Effect; D007114:Immunization; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D014184:Transplantation, Homologous
D019496:Cancer Vaccines