Standard therapies for leukemia such as chemotherapy and hematopoietic stem cell transplantation (HSCT) have significant toxicities due their lack of specificity. Adoptive T cell immunotherapy targeting leukemia-associated antigens has the potential to selectively eliminate leukemic cells with minimal toxicity to normal tissues. Two candidate target antigens, WT1 and Proteinase 3 (PR3 or Myeloblastin), are selectively over expressed in many types of leukemias.
Aims of this project include (1) to determine whether the number and function of WT1 or PR3-specific CD8+ cytotoxic T cells (CTL) in the blood of leukemia patients receiving HSCT correlate with disease remission, (2) to develop reliable and efficient methods for generating WT1 and PR3-specific CTL clones from normal donors using autologous peptide-loaded dendritic cells (DC), (3) to determine whether these clones are able to selectively inhibit the growth of leukemic but not normal cells in both in vivo and in vitro systems, (4) to initiate a Phase I clinical trial in patients with acute leukemia that has relapsed after HSCT to determine whether the transfer of donor-derived WT1-specific CTL clones is safe and can mediate an anti-leukemia effect, and (5) to initiate a similar Phase I trial in relapsed CML patients using PR3-specific clones. Using both WT1 and PR3-derived MHC-peptide tetramers, this proposal seeks to identify specific CTL in the blood of leukemia, patients undergoing HSCT, to isolate and expand high-avidity CTL clones from donor-derived, DC-stimulated cell lines for use in adoptive immunotherapy, and to track WT1 and PR3-specific CTL clones in the blood of patients after infusion. Clones will be assayed for safety and efficacy prior to clinical trials using in vitro colony forming assays and the NOD/SCID mouse model of leukemic engraftment. The long-term goal of this project is to determine whether the adoptive transfer of WT1 or PR3-specific CTL clones is a safe and effective treatment for leukemia. As a Research Associate at the Fred Hutchinson Cancer Research Center and Acting Instructor in the University of Washington Department of Medicine, the candidate is in an ideal environment in which to receive both didactic and practical training related to clinical investigation. In order to develop an independent career in patient-oriented translational research, the candidate will pursue ongoing coursework in clinical trial design, biostatistics, epidemiology, ethics, and the responsible conduct of research, in addition to continuing his preclinical studies and designing and implementing the Phase I clinical trials outlined in this proposal.
