1) Separating GVL from GVHD by boosting regulatory T cells: Low doses of IL-2 are safe to administer and increase the frequency of circulating regulatory T cells. Preliminary data from animal experiments suggests that increased frequencies of regulatory T cells post transplant can reduce incidence and severity of GVHD without preventing GVL effects. We hypothesize that treatment of post transplant recipients of haploidentical stem cells from a mismatched family donor with low dose IL-2 will prevent GVHD but permit the powerful GVL effect from the mismatched transplant leading to lower relapse rates in patients with high risk leukemia. We have now obtained IRB and FDA approval to explore the use of LD IL2 in haploidentical SCT. Donors will be haploidentical family members. The transplant will be partially depleted of T lymphocytes to a dose of 1 x 106 CD3 cells/kg. Recipients will receive LD IL-2 from day 2 for 12 weeks. The main study end point will be the development of grade II-IV acute GVHD with stopping rules for unacceptable day 100 mortality. Secondary outcomes will be relapse and overall survival. 2) Generating clinical grade Leukemia-specific T cells: We are studying expansion techniques for leukemia-specific T cells with peptide mixes of the LAA: 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. A library of K562 cells transfected with a panel of HLA class I and II antigens has been created and will be used to generate T cells recognizing innate and transfected leukemia antigens. 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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