Allogeneic transplantation is an effective therapy for hematologic malignancies and exerts its therapeutic effects through grafts vs leukemia effects. Graft versus leukemia effects are mediated by T-cells directed against minor histocompatibility antigens (mHag). The two best characterized mHag are HA1 and HA2, which are HLA A2 restricted and are preferentially expressed in hematopoietic tissues. We hypothesize that post-transplant vaccination with HA1 or HA2 peptides in combination with GM-CSF in donor-recipient pairs that are HLA-identical, but disparate for the expression of these mHag will result in increased graft vs leukemia effects. Because the proposed conditioning regimen results in profound depletion of host dendritic cells, we hypothesize that vaccination with mHag will not elicit GVHD. In this phase I/II trial we will establish the immunogenicity, biologic effects and toxicity of this approach through the completion of the following specific aims: 1. To determine if HA1/2-peptide vaccinations can induce or enhance short and long-term allogeneic HA1/2-specific T cell immunity in patients with hematologic malignancies undergoing allogeneic transplantation from HLA-identical donors. 2. To evaluate if there is a correlation between the induction or increase of HA1/2 specific immunity and minimal residual disease after HLA-identical transplantation. 3. To evaluate if HA1/2 peptide vaccination induces toxicity, especially acute GVHD after HLA-identical transplantation. We will achieve these specific aims by completion of a phase I/II trial in 25 consecutive transplant recipients, who have the appropriate HLA-type and HA1 or HA2 donor/recipient disparity. The conditioning regimen will consist of fludarabine-melphalan-campath. At day 60, day 100 and day 150 after transplantation, recipients will undergo vaccination with peptide admixed with GM-CSF. Four "dose levels" of vaccination will be evaluated in cohort of 5 patients. In some dose-levels, vaccination will be preceded by infusion of DLI at a dose of 5 x 10[7] CD3 cells/kg. A vaccine related severe GVHD rate of 5% is anticipated and a severe GVHD rate of >20% will not be tolerated. Blood, marrow and skin biopsy samples will be obtained for correlative studies relating to immune reconstitution and minimal residual disease and compared with historical controls.

R21CA101337

2003-06-12

2006-05-31