Allogeneic
bone marrow transplantation (BMT) causes a beneficial graft-versus-
tumor (GVT) immune response that is often associated with
graft-versus-host disease (GVHD). There is substantial interest in developing therapeutic strategies that augment GVT without GVHD. We have demonstrated recently that immunization of BMT donors with cellular
tumor vaccines leads to curative GVT but induces unacceptable GVHD because of the presence of recipient
minor histocompatibility antigens (mHAgs) in whole-cell
tumor vaccines. This study tested the hypothesis that immunization of BMT donors against a defined
tumor-specific
antigen with a
vaccine not containing recipient mHAgs would help to separate the two responses by enhancing GVT activity without exacerbating GVHD, even when cellular
vaccines were used after BMT. Recipient strain C57BL/6
fibrosarcoma cells engineered to express the well-characterized model
tumor antigen,
influenza nucleoprotein (NP), were used in these studies. C3H.SW donors were immunized against NP prior to BMT, and cytolytic T cells were transferred along with bone marrow into irradiated H-2-matched, mHAg-mismatched C57BL/6 recipients with established micrometastatic 205-NP
tumors. Donor immunization led to a significant increase in GVT activity, as measured by reduction in
tumor growth and enhanced survival. However, deaths in recipients of
tumor antigen-specific immune BMT ultimately occurred because of the growth of
antigen-loss variants; such
tumor growth did not occur in animals receiving BMT from donors treated with whole-cell
vaccines. Donor immunization did not lead to an exacerbation of GVHD, even when BMT recipients received additional immunization after BMT with a 205-NP "whole"
tumor cell
vaccine (which was shown to induce fatal GVHD when used for donor immunization). In conclusion, immunization of allogeneic BMT donors against a
tumor-specific
antigen significantly enhances GVT activity without an associated exacerbation of GVHD.