GRAFT VERSUS LEUKEMIA IMMUNOTHERAPY

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Allogeneic bone marrow transplantation is a highly effective therapeutic approach to curing several forms of leukemia, particularly acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML). The two largest risk factors involved in a successful transplant are the occurrence of either graft-versus-host disease (GVHD) or leukemic relapse, with the incidence of the former inversely affecting the incidence of the latter. Theoretically, this occurs because the donor T cells in the marrow inoculum responsible for GVHD are directed to recipient histocompatibility antigens that may also be present on residual leukemia cells and thereby reduces the risk of relapse. However, since GVHD is also quite devastating to the recipient, the essential question becomes whether GVHD-reactive T cells can be selectively depleted rom an inoculum, while preserving graft-versus- leukemia (GVL) potential. To investigate this question, we have established an experimental allogeneic bone marrow transplantation murine model in which the donor/recipient strains are MHC-compatible, but GVHD can be induced against multiple minor histocompatibility antigens. Challenge of recipients with a lethal dose of myeloid leukemia allows us to assess the components required for possible immunotherapeutic resistance to the leukemia, as well as how this might best be accomplished while avoiding GVHD. To approach this general goal, we specifically will concentrate our efforts on: 1) the immunological basis for GVL activity in a syngeneic B6- >B6 irradiated bone marrow transplantation model with challenge of c-myc transformed myeloid leukemia cells; and 2) the immunological basis for GVL activity in a minor H antigen allogeneic C3H.SW->B6 irradiated bone marrow transplantation model with challenge of c-myc transformed myeloid leukemia cells.