Minor Histocompatilibity Vaccination After Allo-Transpl*

描述（申请人提供）：同种异体移植是一种有效的血液恶性肿瘤治疗方法，通过移植物对抗白血病效应发挥其治疗作用。移植物抗白血病效应是由t细胞直接针对次要组织相容性抗原（mHag）介导的。最具特征的两种mHag是HA1和HA2，它们受HLA A2限制，优先在造血组织中表达。我们假设，移植后接种HA1或HA2肽与GM-CSF结合的供体-受体对hla相同，但这些mHag的表达不同，将导致移植物抗白血病效果增加。由于提出的调节方案导致宿主树突状细胞的严重消耗，我们假设接种mHag不会引发GVHD。在这个I/II期试验中，我们将通过完成以下具体目标来确定这种方法的免疫原性、生物效应和毒性：确定ha1 /2肽疫苗接种是否可以诱导或增强接受同种hla供体异体移植的恶性血液病患者的短期和长期同种异体ha1 /2特异性T细胞免疫。2. 评估同种hla移植后HA1/2特异性免疫的诱导或增加与最小残留病之间是否存在相关性。3. 评估HA1/2肽疫苗接种是否会引起毒性，特别是同种hla移植后的急性GVHD。我们将通过在25名具有适当hla型和HA1或HA2供者/受者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。调理方案将包括氟达拉滨-美法兰-坎帕斯。在移植后的第60天、第100天和第150天，受体将接受与GM-CSF混合的肽疫苗接种。将在5名患者队列中评估4种“剂量水平”的疫苗接种。在某些剂量水平下，疫苗接种前将以5 × 10[7] CD3细胞/kg的剂量输注DLI。预计与疫苗相关的严重GVHD率为5%，严重GVHD率为100 - 20%是不能容忍的。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疾病相关的研究，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.