1.HLA mismatched alloresponses: Exploiting the GVL potential of the haploidentical donor: We previously characterized the mismatched alloresponse in man and showed that T-cell responses to allogeneic targets arise predominantly from the nave pool of post-thymic T cells. We are continuing a trial of haploidentical donor lymphocyte transfusions with stem cell rescue in patients who relapse after SCT. We have shown in 4 patients a powerful graft-versus-marrow effect of these infusions but patients all died later from recurrence of disease or complications associated with poor hematopoietic recovery. This study is ongoing. 2.Generating clinical grade Leukemia-specific T cells: We are studying expansion techniques for leukemia-specific T cells with peptide mixes of WT1, proteinase 3, PRAME, MAGE3, and aurora-A kinase.
The aim i s to develop a clinical grade system to generate off the shelf donor or third party tumor-specific T cells for infusion in SCT recipients to treat or prevent relapse. Preliminary data indicates that individual responses to the tumor peptides are variable, but that all healthy donors tested make a response to a mix of LAA peptides indicating that this technique can be developed as a robust clinically applicable approach to treating patients at high risk of relapse after SCT with leukemia reactive T cell infusions. Translational work to expand the process to clinical scale are under way. To further increase the clinical potential of adoptive T cell therapy we have constructed a panel of artificial antigen presenting cells (AAPC) based upon the K562 CML cell line. These AAPC have the potential to induce T cell responses to antigens presented by gene inserted HAL A2 and HLA DR15 together with CD80 and CD81 costimulatory molecules. However we found that K562 cells produce a suppressor which blocks T cell proliferation. Suppression can be blocked by fixation which preserves the stimulatory function of the AAPC. We are currently studying the nature of T cell suppression by K562 cells and continuing to develop a clinical grade off the shelf AAPC for expansion of T cells for adoptive therapy. 3. New antigen discovery: In conjunction with Dr Chris Hourigan we are screening AML samples obtained from collaboration with Vanderbilt University (Dr Strickland) to characterize the pattern of LAA presentation on AML stem cells and identify new LAA. These findings will assist the construction of a broad antigen library capable of inducing T cell responses to the majority of AML patients.
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