This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of these proposed studies is to improve leukemia treatment using targeted adoptive immunotherapy. A vital element contributing to the efficacy of HSCT is the graft-versus-leukemia (GVL) effect, as evidenced by the anti-tumor activity of both donor lymphocyte infusions (DLI) in the treatment of relapsed chronic myeloid leukemia (CML) post-HSCT and nonmyeloablative HSCT. An unfortunate side effect in these settings, however, is the high rate of associated acute and chronic graft-versus-host disease (GVHD) resulting in significant morbidity and mortality. Thus, one goal of current HSCT research is to maximize the GVL effect while minimizing the chances of significant GVHD. This might be accomplished by infusing T cells that preferentially recognize and lyse leukemic host cells as compared to normal non-malignant host tissues. Much effort has been focused on identifying proteins expressed either exclusively or preferentially in leukemic cells that can serve as targets of cytotoxic T lymphocyte (CTL) responses. Two proteins - WT1 and Proteinase 3 (PR3, or Myeloblastin) - have recently been described as potentially targetable antigens associated with acute leukemias and CML. In fact, significant numbers of functional CD8+ CTL specific for an HLA-A2 restricted epitope of PR3 have been identified in a fraction of CML patients who maintain normal hematopoiesis and have successfully responded to either interferon therapy or HSCT, suggesting that these PR3-specific CTL are non-toxic and could be mediating a GVL effect in vivo. In addition, recent vaccine trials with both WT1 and PR3 peptides have appeared to show some preliminary evidence of clinical effects in patients with leukemia. The work being proposed includes Phase I/II studies that will examine the safety and potential efficacy of infusing CD8+ T cell clones specific for PR3 in patients with leukemia that has relapsed after HSCT, who have been selected for the trial based on the poor prognosis of such patients and lack of effective treatment options. The methods currently being used to generate T cells for these clinical trials are based on similar adoptive immunotherapy trials underway in our program targeting other antigens and diseases.
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