Allografting for Lukemia

白血病同种异体移植

• 批准号: 8260361
• 负责人: Robert S Negrin
• 金额: $ 26.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260361
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Age; Alloantigen; Allogenic; Allografting; Animals; Antithymoglobulin; Autoimmune Diseases; B-Lymphocytes; Biology; Bone Marrow Transplantation; Cell Transplantation; Cell physiology; Cells; Cellular biology; Cessation of life; Chronic; Chronic Disease; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Cyclosporine; Development; Disease; Dose; Dysmyelopoietic Syndromes; Elderly; Engraftment; Excision; Graft vs Tumor Effect; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic; Homologous Transplantation; Immune; Immunosuppression; Immunotherapy; Individual; Institution; Killer Cells; Lymphatic Irradiation; MS4A1 gene; Maintenance; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Medical; Monoclonal Antibody CD20; Morbidity - disease rate; Myeloproliferative disease; Organ Transplantation; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Play; Population; Program Research Project Grants; Reaction; Recurrent disease; Regimen; Regulatory T-Lymphocyte; Relapse; Research Personnel; Risk; Role; Siblings; Sirolimus; Solid; T-Lymphocyte; Testing; Tissues; Toxic effect; Translating; Translations; Transplantation; Whole-Body Irradiation; Work; chemotherapy; chronic graft versus host disease; cytokine; disorder risk; effective therapy; efficacy testing; fludarabine; graft vs host disease; high risk; improved; leukemia/lymphoma; mycophenolate mofetil; neoplastic cell; novel; novel strategies; prophylactic; rituximab; treatment strategy; tumor

Project 1 will serve to translate concepts developed in other Projects to the clinic and build upon our prior work on developing novel strategies to improve outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). The concepts developed will likely benefit patients with serious hematological malignancies but could also provide novel treatment strategies for patients with severe autoimmune disorders and those undergoing solid organ transplantation. Therefore, the concepts developed are broad and have significant implications for a number of fields. We will build upon our successful translation of the studies developed in Project 4 where the novel non-myeloablative regimen of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) has been explored with marked reduction in acute graft vs host disease (GVHD) risk with retained graft vs tumor (GVT) responses, The TLI/ATG regimen will be tested as compared to standard chemotherapy in older (ages 50-75) patients with AML in first CR in a multi-institutional phase III trial with those patients with HLA matched sibling donors receiving allogeneic HCT and those without treated with standard chemotherapy (Specific Aim #1). We will attempt to augment the TLI/ATG regimen in two important ways by utilizing prophylactic administration of cytokine induced killer (CIK) cells developed in Project 3 in an effort to reduce relapse risk in patients with high risk myeloid malignancies (Specific Aim #2). A second approach will be to utilize the anti-CD20 monoclonal antibody rituximab in combination with TLI/ATG in patients with mantle cell lymphoma and chronic lymphocytic leukemia to explore whether this combined approach will reduce chronic GVHD and disease relapse (Specific Aim #3). Finally we will translate basic observations in regulatory T cell biology where we have observed that cyclosporine A has a major impact on Treg function whereas rapamycin and MMF do not. We will test the combination of RAPA/MMF following myeloablative HCT in patients with high risk malignancies in an effort to reduce GVHD risk. This Project interacts with all of the other Projects and utilizes all four of the Cores.

项目 1 将致力于将其他项目中开发的概念转化为临床，并建立在我们之前的基础上 致力于开发新策略以改善接受同种异体造血的患者的预后 细胞移植（HCT）。所开发的概念可能会使患有严重血液病的患者受益 恶性肿瘤，但也可以为患有严重自身免疫性疾病的患者提供新的治疗策略 疾病和接受实体器官移植的人。因此，所开发的概念是广泛的 并对许多领域产生重大影响。我们将在成功翻译 项目 4 中开展的研究，其中新型非清髓性全淋巴照射 (TLI) 方案 抗胸腺细胞球蛋白 (ATG) 已被探索可显着减少急性移植物抗宿主病 (GVHD) 风险与保留的移植物抗肿瘤 (GVT) 反应，TLI/ATG 方案将进行比较测试 在多机构 III 期临床试验中，对首次 CR 的老年（50-75 岁）AML 患者进行标准化疗 对接受同种异体 HCT 的 HLA 匹配的兄弟姐妹捐赠者和未接受治疗的患者进行的试验 标准化疗（具体目标#1）。我们将尝试在两个方面增强 TLI/ATG 方案 利用预防性施用细胞因子诱导杀伤（CIK）细胞的重要方法 项目 3 致力于降低高危骨髓恶性肿瘤患者的复发风险（具体目标 #2）。 第二种方法是结合使用抗 CD20 单克隆抗体利妥昔单抗 TLI/ATG 在套细胞淋巴瘤和慢性淋巴细胞白血病患者中的应用探讨这是否 联合方法将减少慢性 GVHD 和疾病复发（具体目标#3）。最后我们将 转化调节性 T 细胞生物学中的基本观察结果，我们观察到环孢菌素 A 具有 对 Treg 功能有重大影响，而雷帕霉素和 MMF 则不会。我们将测试以下组合 高危恶性肿瘤患者清髓性 HCT 后的 RAPA/MMF 旨在减少 GVHD 风险。该项目与所有其他项目交互并利用所有四个核心。