Despite the intensive preparative regiment, relapse of the malignancy remains the most frequent cause of failure for patients who undergo allogeneic bone marrow transplantation (BMT) for the treatment of acute and chronic leukemia. Clinical and experimental studies have established that donor T cells specific for recipient minor histocompatibility (H) antigens initiate both graft-versus-host-disease (GVHD) and graft-versus-leukemia (GVL) reactions and contribute to the complete elimination of leukemia after allogeneic BMT. Studies by our lab evaluating the adoptive transfer of human T cell clones as therapy for viral diseases have led to the development of methods to propagate antigen-specific T cells to numbers sufficient to transfer immunity and methods to introduce genes into T cells including an inducible """"""""suicide"""""""" gene to permit the ablation of transferred T cells if they cause toxicity to the host. These developments combined with studies that have identified donor T cell clones specific for recipient minor H antigens that are expressed selectively on hematopoietic cells including leukemic blasts provide the rationale for this proposal to evaluate the adoptive transfer of gene-modified T cells and T cell clones specific for minor H antigens to preferentially augment GVL activity after allogeneic BMT.
The specific aims are: To determine the safety and antileukemic effects of adoptively transferred polyclonal donor T lymphocytes modified to express the HSV thymidine kinase (TK) gene in patients with relapse of CML after allogeneic bone marrow transplant. To evaluate in patients with post transplant relapse of AML and ALL, the safety and antileukemic effects of adoptive immunotherapy with donor-derived HSV-TK modified T cell clones specific for minor histocompatibility antigens expressed by recipient hematopoietic cells but with limited or absent expression on nonhematopoietic tissues. To evaluate the antileukemic efficacy of CD8+ and CD4+ T cell clones specific for minor histocompatibility antigens in the NOD/SCID mouse model of human leukemia. To identify the genes encoding minor histocompatibility antigens recognized by CD8+ T cell clones which exhibit antileukemic activity in patients or in NOD/SCID mice.
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