Allografting for Lukemia

白血病同种异体移植

• 批准号: 7212894
• 负责人: Robert S Negrin
• 金额: $ 21.3万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212894
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Age; Alloantigen; Allogenic; Allografting; Animals; Antithymoglobulin; Autoimmune Diseases; B-Lymphocytes; Biology; Cell Transplantation; Cell physiology; Cells; Cellular biology; Cessation of life; Chronic; Chronic Lymphocytic Leukemia; Clinic; Clinical; Clinical Trials; Condition; 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; Numbers; Organ Transplantation; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Play; Population; Program Research Project Grants; Range; Reaction; Recurrent disease; Relapse; Research Personnel; Risk; Role; Siblings; Sirolimus; Solid; Standards of Weights and Measures; T-Lymphocyte; Testing; Tissues; Toxic effect; Translating; Translations; Transplantation; Treatment Protocols; Whole-Body Irradiation; Work; chemotherapy; chronic graft versus host disease; concept; cytokine; disorder risk; fludarabine; fluorouracil/methotrexate/mitoxantrone protocol; graft vs host disease; improved; mycophenolate mofetil; neoplastic cell; novel; novel strategies; prophylactic; rituximab; 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将有助于将其他项目中开发的概念转化为诊所，并在我们先前的 开发新型策略以改善接受同种异体造血的患者的结局的努力 细胞移植（HCT）。发展的概念可能会使严重血液学患者受益 恶性肿瘤，但也可以为严重自身免疫的患者提供新颖的治疗策略 疾病和接受固体器官移植的人。因此，发展的概念很广泛 并对许多字段具有重大影响。我们将基于我们成功翻译的 在项目4中开发的研究，其中新型的总淋巴辐射的非毛囊治疗方案（TLI） 和抗胸腺细胞球蛋白（ATG）已被探索，急性移植与宿主病明显降低 （GVHD）保留的移植物与肿瘤（GVT）反应的风险，将测试TLI/ATG方案 在多机构的III期中，在第一期CR中年龄较大（50-75岁）AML的标准化疗（50-75岁） 与那些匹配同种异体HCT的HLA匹配的兄弟姐妹供体的患者和未经治疗的患者进行试验 使用标准化疗（特定目标＃1）。我们将尝试将TLI/ATG方案增加两次 利用细胞因子诱导杀伤（CIK）细胞的预防性给药中的重要方法 项目3是为了减少髓样恶性肿瘤高风险患者的复发风险（特定目标2）。 第二种方法是利用抗CD20单克隆抗体利妥昔单抗和 地幔细胞淋巴瘤和慢性淋巴细胞性白血病患者的TLI/ATG探讨这是否是 联合方法将减少慢性GVHD和疾病复发（特定目的＃3）。最后我们会的 在调节性T细胞生物学中翻译基本观察结果，我们观察到环孢素A具有A 对Treg功能的主要影响，而雷帕霉素和MMF则没有。我们将测试组合 高风险恶性肿瘤患者的骨髓性HCT后RAPA/MMF，以减少GVHD 风险。该项目与所有其他项目互动，并利用了所有四个内核。