Immune manipulation to generate tumor immunity and regulate GVHD after allogeneic HCT

项目摘要 疾病复发和移植物抗宿主病（GVHD）仍然是改善预后的主要障碍 用于接受异基因造血细胞移植的恶性血液病患者。项目1 将开发和实施一系列新的临床试验，以解决这些问题的3个具体目标。要求1 侧重于基于免疫的策略，以防止接受HCT的骨髓恶性肿瘤患者复发。 其中包括临床研究，以检查伊匹单抗检查点阻断的安全性和影响 在基于基因组的高复发风险的骨髓恶性肿瘤患者中，在allo-HCT后早期给予 在移植前进行分析。我们还将完成一项前瞻性2期安慰剂对照随机试验， 给予经遗传工程改造以分泌GM-CSF（GVAX）的自体白血病细胞疫苗 对进入allo-HCT的患有活动性疾病的髓性白血病患者具有特异性。第三次审判将 评估HCT后设计用于靶向白血病特异性 基于受体白血病细胞基因组特征的新抗原和次要组织相容性抗原 与正常供体细胞相比。目标2关注尽管allo-HCT但复发的患者，并将测试 检查点阻断与过继细胞治疗相结合的策略的有效性和安全性 操纵以耗尽调节性T细胞。目的3将确定联合IL-2和IL-4的安全性和有效性。 类固醇难治性慢性GVHD患者的伊替尼治疗。

Project Summary Disease relapse and graft versus host disease (GVHD) continue to be major obstacles to improving outcomes for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation. Project 1 will develop and implement a series of novel clinical trials to address these issues in 3 Specific Aims. Aim 1 focuses on immune based strategies to prevent relapse for patients with myeloid malignancies undergoing HCT. These include clinical studies to examine the safety and impact of checkpoint blockade with ipilumumab administered early after allo-HCT in patients with myeloid malignancies at high risk of relapse based on genomic profiling prior to transplant. We will also complete a prospective phase 2 placebo controlled randomized trial of autologous leukemia cell vaccines genetically engineered to secrete GM-CSF (GVAX) administered prophylactically to patients with myeloid leukemias entering allo-HCT with active disease. A third trial will evaluate the impact of novel personal peptide vaccines after HCT designed to target leukemia-specific neoantigens and minor histocompatibility antigens based on genomic characterization of recipient leukemia cells compared with normal donor cells. Aim 2 focuses on patients who have relapsed despite allo-HCT and will test the efficacy and safety of a strategy that combines checkpoint blockade with adoptive cellular therapy manipulated to deplete regulatory T cells. Aim 3 will determine the safety and efficacy of combined IL-2 and ibrutinib therapy in patients with steroid-refractory chronic GVHD.