Prevention and Treatment of Graft-Versus-Host Disease

移植物抗宿主病的预防和治疗

• 批准号: 8277819
• 负责人: PAUL J MARTIN
• 金额: $ 38.55万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277819
• 关键词: Acute Graft Versus Host Disease; Alloantigen; Allogenic; Antibodies; Antigen-Presenting Cells; Beclomethasone; Blood; Body Surface; Bone Marrow Transplantation; CD28 gene; Cell Transplantation; Characteristics; Clinical; Clinical Research; Clinical Trials; Complication; Development; Disease; Dose; Drug Kinetics; Enrollment; Exanthema; Feces; Funding; Gastrointestinal tract structure; Glucocorticoids; Goals; Hematopoietic; Human; Immune; Immunosuppressive Agents; Incidence; Intestines; Laboratory Study; Lead; Liver; Malignant Neoplasms; Methods; Methotrexate; Methylprednisolone; Multiple Myeloma; Mus; Newly Diagnosed; Opportunistic Infections; Oral; Oral Administration; Organ; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Prednisone; Prevention; Public Health; Randomized Clinical Trials; Reaction; Recurrence; Regimen; Research; Research Personnel; Resolution; Risk; Safety; Steroids; T-Cell Depletion; T-Lymphocyte; Testing; Time; Toxicology; Withdrawal; adult leukemia; alemtuzumab; base; conditioning; effective therapy; gastrointestinal; graft vs host disease; improved; in vivo; intestinal crypt; leukemia/lymphoma; nonhuman primate; phase 1 study; phase 2 study; prevent; programs; prophylactic; research study; safety testing

Project 3 Prevention and Treatment of Graft-versus-host Disease: The goal of this project is to improve survival after allogeneic hematopoietic cell transplantation (HCT) by more effective prevention and treatment of acute graft-versus-host disease (GVHD). Aim 1 is directed toward prevention of GVHD through prophylactic oral administration of a topically active glucocorticoid that has little systemic effect. Separate phase II clinical trials will be carried out among patients who have myeloablative and non-myeloablative conditioning regimens before HCT. These studies will test the hypothesis that prophylactic administration of beclomethasone diproprionate can greatly decrease the incidence of GVHD involving the gastro-intestinal tract and possibly other target organs as well. Aim 2 is directed toward decreasing the amount of steroid treatment needed to control GVHD among patients who develop this complication after HCT. Patients who develop acute GVHD after HCT with a myeloablative conditioning regimen will be treated with low-dose alemtuzumab to test the hypothesis that depletion of T cells after administration of the antibody will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of opportunistic infections. Patients who develop GVHD after HCT with a non- myeloablative conditioning regimen will be treated with low-dose methotrexate to test the hypothesis that the effects of this drug on donor T cells will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of recurrent malignancy. In Aim 3, phase I and phase II clinical trials will be carried out to test the hypothesis that administration of a CD28-specific antibody is effective for treatment or prevention of acute GVHD, as suggested by previous laboratory studies. Patients with GVHD that cannot be controlled by currently available treatments will be enrolled in a phase I clinical trial. If results of the phase I study are encouraging, then a phase II study will be carried out to test whether administration of the antibody can prevent GVHD in humans. Relevance to Public Health: The studies in this project could lead to the development of more effective methods for preventing or treating harmful immune reactions that can occur when blood or marrow transplantation is used to treat leukemia, lymphoma, myeloma and other related disorders. Successful development of such methods would improve the safety and applicability of blood or marrow transplantation for treatment of these diseases. '

项目3预防和治疗移植物与宿主病：该项目的目的是改善 通过更有效的预防和治疗，同种异性造血细胞移植（HCT）后的生存 急性移植物抗宿主病（GVHD）。 AIM 1致力于预防GVHD 预防性的口服局部活性糖皮质激素，几乎没有全身作用。分离 II期临床试验将在具有骨髓性和非肌瘤的患者中进行 HCT之前的调理方案。这些研究将检验以下假设 供应偶氮替代物可以大大降低涉及胃肠道的GVHD的发生率 区域，可能还有其他目标器官。 AIM 2针对减少类固醇的量 在HCT后发生这种并发症的患者中需要控制GVHD。患者 HCT后使用髓能条件方案进行急性GVHD，将用低剂量治疗 Alemtuzumab检验了以下假设：抗体给药后T细胞的耗竭将 加速该疾病的分辨率，并允许更快地戒断类固醇治疗，而无需 增加机会性感染的风险。 HCT后患有GVHD的患者 脊髓含量低甲氨蝶呤将接受骨髓性调节方案，以检验以下假设。 该药物对供体T细胞的影响将加速该疾病的分辨率，并允许更快 戒断类固醇治疗，而不会增加复发性恶性肿瘤的风险。在AIM 3，第一阶段和 将进行II期临床试验，以检验施用CD28特异性抗体的假设 如先前的实验室研究所示，可有效治疗或预防急性GVHD。患者 使用当前可用治疗无法控制的GVHD将在I期临床上注册 审判。如果I阶段研究的结果令人鼓舞，那么将进行第二阶段研究以测试是否是否 抗体的给药可以防止人类的GVHD。 与公共卫生有关：该项目的研究可能导致更有效的发展 预防或治疗血液或骨髓时可能发生的有害免疫反应的方法 移植用于治疗白血病，淋巴瘤，骨髓瘤和其他相关疾病。成功的 这种方法的开发将提高血液或骨髓移植的安全性和适用性 治疗这些疾病。 '