Minor Histocompatilibity Vaccination After Allo-Transpl*

描述（由申请人提供）：同种异体移植是恶性血液病的有效治疗方法，通过移植物与白血病效应发挥其治疗作用。移植物抗白血病效应由针对次要组织相容性抗原（mHag）的T细胞介导。两种最佳表征的mHag是HA 1和HA 2，它们是HLA A2限制性的并且优先在造血组织中表达。我们假设，移植后接种HA 1或HA 2肽与GM-CSF的组合，在HLA相同的供体-受体对中，但这些mHag的表达不同，将导致增加的移植物对白血病的影响。由于所提出的预处理方案导致宿主树突状细胞的深度耗竭，我们假设用mHag接种不会引起GVHD。在本I/II期试验中，我们将通过完成以下具体目标来确定该方法的免疫原性、生物学效应和毒性：1.确定HA 1/2肽疫苗接种是否可以诱导或增强接受HLA相同供体异基因移植的恶性血液病患者的短期和长期异基因HA 1/2特异性T细胞免疫。2.目的探讨HLA相合移植后HA 1/2特异性免疫的诱导或增强与微小残留病的关系。3.评估HA 1/2肽疫苗接种是否诱导毒性，尤其是HLA相合移植后的急性GVHD。我们将通过在25名具有适当HLA型和HA 1或HA 2供体/受体差异的连续移植受者中完成I/II期试验来实现这些具体目标。预处理方案将由氟达拉滨-美法仑-坎帕组成。在移植后第60天、第100天和第150天，接受者将接受与GM-CSF混合的肽的疫苗接种。将在5名患者的队列中评价4个“剂量水平”的疫苗接种。在某些剂量水平下，接种疫苗前将以5 x 10[7] CD 3细胞/kg的剂量输注DLI。预期疫苗相关的严重GVHD发生率为5%，严重GVHD发生率>20%将不能耐受。将获得血液、骨髓和皮肤活检样本，用于与免疫重建和微小残留病相关的相关研究，并与历史对照进行比较。

DESCRIPTION (provided by applicant): 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.