The efficacy of allogeneic bone marrow transplantation is limited by relapse and by treatment-related mortality. Efforts to reduce relapse by increasing preparative regimen intensity often lead to increased toxicity. Conversely, reductions in morbidity and mortality that can be achieved by removing T-cells from the graft are often accompanied by increases in relapse rates. We hypothesize that improvements in the specific leukemia cytoreductive efficacy of the preparative regimen or specific graft versus leukemia effects after transplant each could lead to improvements in outcome, if they could be accomplished safely. Therefore, our over-arching goal is to develop specific-immunotherapeutic approaches to achieve these ends. First, methods to generate highly potent, leuke-mia- specific donor T-cells (in vitro and via vaccination) will be developed, using either oncogene product fusion-peptide analogues or analogues of overexpressed leukemia associated proteins (WT-1), as targets. Second, specific radioimmunotherapy using beta-emitting anti-CD33 antibody will be used to improve pre-transplant preparation in a """"""""mini-transplant"""""""" setting. In our last three years, we have been able to achieve the following goals: a) Quantitative methods to identify peptides capable of binding human HLA were developed. b) CML fusion-peptides from b3a2 and e1a2 peptides were identified that bind with high affinity to human HLA. c) Immunogenicity of these peptides was shown in vitro. d) A Phase I trial of b3a2 peptides was successfully completed and a phase II trial was initiated. These peptides are immunogenic, but not very potent. We now propose to extend and broaden these findings using new methods and models with goals of increasing immunogenicity and better understanding how to use these new agents.
The specific aims are: 1) To screen, select, produce and evaluate the binding and immunogenicity of synthetic peptide analogues of CML fusion point peptides and of WT-1 peptides. 2) To examine whether the analogues are heteroclitic (i.e. result in immune cross reactivity to the native sequences). 3) To test the potency of the native and analogue peptides in animal models of leukemia (as prophylaxis; as therapy; as stimulators of DLI). 4) To conduct clinical trials of the analogue peptides. 5) To provide laboratory correlative data and support for a radioimmunotherapy based mini-transplant regimen.
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