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移植物抗宿主病的防治：本项目的目标是提高 通过更有效的预防和治疗，提高异基因造血细胞移植（HCT）后的生存率 急性移植物抗宿主病（GVHD）目的1是通过以下途径预防GVHD： 预防性口服局部活性糖皮质激素，全身作用小。单独 II期临床试验将在清髓性和非清髓性患者中进行， HCT前预处理方案。这些研究将检验预防性给予 二丙酸倍氯米松可显著降低GVHD累及胃肠道的发生率 以及其他可能的靶器官。目标2是针对减少类固醇的量 在HCT后发生GVHD并发症的患者中，需要进行控制GVHD的治疗。的患者 在HCT后用清髓性预处理方案发生急性GVHD的患者将接受低剂量 Alemtuzumab检测抗体给药后T细胞耗竭将 加速疾病的消退，并允许更快地停止类固醇治疗， 增加机会性感染的风险。HCT后发生GVHD的患者， 清髓性预处理方案将用低剂量甲氨蝶呤治疗，以检验以下假设： 这种药物对供体T细胞的作用将加速疾病的消退， 停止类固醇治疗，不会增加恶性肿瘤复发的风险。在目标3第一阶段， 将进行II期临床试验，以检验给予CD28特异性抗体 有效治疗或预防急性GVHD，如先前的实验室研究所建议的。患者 目前可用治疗无法控制的GVHD患者将入组I期临床试验， 审判如果第一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 抗体的施用可以预防人中的GVHD。 与公共卫生的相关性：本项目的研究可能导致开发更有效的 用于预防或治疗当血液或骨髓 移植用于治疗白血病、淋巴瘤、骨髓瘤和其它相关疾病。成功 这些方法的发展将提高血液或骨髓移植的安全性和适用性 用于治疗这些疾病。'