Relapse of the malignancy remains a major cause of failure for patients who undergo allogeneic hematopoietic stem cell (HSC) transplantation for the treatment of acute and chronic leukemia. 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 HSC transplant. Infusions of donor peripheral blood mononuclear cells (PBMC) have induced complete remissions in many patients with posttransplant relapse and have demonstrated the antileukemic potential of donor T cells, but such infusions have also caused significant GVHD. Thus, the use of T cell therapy to improve the success rate of allogeneic HSC transplantation will require the identification of effector cells that can mediate a more potent and more selective GVL effect. Studies by the applicant have demonstrated that donor-derived CD8+ cytotoxic T cell (CTL) clones specific for tissue-restricted minor H antigens can be isolated from HSC transplant recipients. These CTL are cytolytic against leukemic cells in vitro, and will eliminate the leukemic progenitor cell necessary for engraftment of human AML in NOD/SCID mice. The hypothesis to be evaluated in this proposal in preclinical and clinical studies is that the isolation from allogeneic HSC transplant recipients of T cell clones specific for recipient minor H antigens and the molecular identification of target antigens selectively expressed in hematopoietic cells will permit the development of specific adoptive immunotherapy to enhance GVL effects without inducing GVHD.
The specific aims are: 1. To generate and characterize CD8+ and CD4+ T cell clones specific for human minor histocompatibility antigens expressed by hematopoietic cells including leukemic blasts. 2. 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. 3. To identify the genes encoding tissue- restricted minor histocompatibility antigens recognized by CD8+ T cell clones which exhibit antileukemic activity in patients or in NOD/SCID mice. 4. To evaluate in patients with posttransplant relapse of AML and ALL, the safety and antileukemic effects of adoptive immunotherapy with 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.
| Akatsuka, Y; Warren, E H; Brickner, A G et al. (2001) Determination of intronic sequences adjacent to an exon using polymerase chain reaction and genomic DNA library constructed by TA cloning. Anal Biochem 289:289-92 |
