The object of the proposed studies is to determine whether tumor antigen vaccination of donors of MHC matched hematopoietic cell transplants (HCT) can increase graft-versus-tumor (GVT) activity without increasing graft- versus-host disease (GVHD) in both pre-clinical and clinical studies. In the case of B cell lymphomas, we will use vaccination with idiotype peptides derived from the B-cell receptor (BCR) CDR3 region to immunize against the tumors. In the case of myeloid leukemia, we will use vaccination with the WT-1 peptide that is an overexpressed leukemia tumor antigen. Mouse and human recipients with B cell lymphoma will be conditioned with total lymphoid irradiation and anti-thymocyte antibodies (an acute GVHD protective regimen), and mixed chimeras will receive phenotypic CD8+ memory T (TM) cell donor lymphocyte infusions (DLI) that mediate GVT without GVHD from idiotype immunized donors. Sorted CD8+ TM cells express the CD8+CD44hi phenotype in mice, and CD8+CD45R0+CD45RA- phenotype in humans. It is also expected that the DLI will induce conversion from mixed to complete chimerism, and that the tumor antigen immunized TM cell DLI will mediate potent GVT activity as compared to the nonimmunized TM cell DLI. Booster vaccinations of recipients is expected to increase anti-tumor activity even further. GVHD will be minimized in myeloid leukemia transplant recipients given myeloablative conditioning by using T cell depleted (TCD) CD34+ selected grafts combined with donor CD8+ TM cells. The infusion of the latter cells is expected to improve immune reconstitution and GVT activity as compared to TCD CD34+ selected grafts alone. In summary, we will use strategies developed in our laboratory to prevent GVHD, and tumor antigen immunization to increase GVT activity such that overall and event-free survival is increased in the proposed preclinical and clinical studies.
We have developed strategies to reduce GVHD by use of the TLI and ATG conditioning regimen and the use of CD8+ memory T cells for DLI treatment of HCT recipients. This approach will be combined with immunization of donors and recipients against tumor antigens to increase GVT activity without increasing GVHD.
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