Allogeneic marrow transplantation is thought to be curative in leukemia, in part, because of a graft-versus-leukemia (GVL) effect derived from the adoptive transfer of immunocompetent cells in the donor graft. Despite the antileukemia effect conferred by the allogeneic graft, relapse remains a major cause of treatment failure. Disease relapse is generally thought to evolve from occult malignant cells which are undetectable using standard clinical criteria. Sensitive detection of minimal residual disease is possible using molecular biologic techniques which are able to exploit specific chromosomal abnormalities in hematologic neoplasias as markers of disease recurrence. The objective of the planned research is to define the clinical and biologic significance of minimal residual disease after allogeneic marrow transplantation and develop therapeutic strategies to augment antileukemia reactivity to reduce disease relapse. A murine leukemia model analogous to T cell acute lymphoblastic leukemia in man will be used in these studies. The hypothesis to be tested is that the antileukemia effect of the donor graft can be enhanced by the in vivo administration of selected cytokines to recipient animals with minimal residual disease in the post-transplant period, and that early therapeutic intervention will prevent relapse and lead to cure.
The specific aims of the proposed research are: 1) To develop and test an animal model for the detection of minimal residual disease after allogeneic marrow transplantation before the development of clinically overt disease. Detection of residual leukemia will be facilitated by the use of the polymerase chain reaction (PCR) and sequence specific oligonucleotide probe hybridization (SSOPH) using Thy 1 allelic differences to discriminate host leukemic from nonleukemic donor/recipient cells. 2) To study how alter actions in intensity of the pre-transplant conditioning regimen and in the T cell content of the donor graft influence the incidence of minimal residual disease, the subsequent progression to overt clinical relapse and the post-transplant therapeutic treatment window. 3) To assess the therapeutic efficacy of selected cytokines (e.g., alpha interferon and interleukin-2 alone and in combination) when administered to animals with minimal disease to test the hypothesis. The eventual goal is to use this clinically relevant model in the design of rational clinical trials which can be implemented in an existing bone marrow transplant program.
