Prevention and Treatment of Graft-Versus-Host Disease

移植物抗宿主病的预防和治疗

基本信息

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
项目类别：
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

项目摘要

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 移植物抗宿主病的预防和治疗：该项目的目标是改善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）。目标 1 旨在通过以下方式预防 GVHD：预防性口服局部活性糖皮质激素，全身作用很小。分离 II期临床试验将在接受清髓性和非清髓性治疗的患者中进行 HCT 前的预处理方案。这些研究将检验以下假设：预防性施用二丙酸倍氯米松可大大降低胃肠道GVHD的发生率道以及可能的其他靶器官。目标 2 旨在减少类固醇的用量 HCT 后出现这种并发症的患者需要治疗来控制 GVHD。患者谁采用清髓性预处理方案的 HCT 后发生急性 GVHD 将采用低剂量治疗 alemtuzumab 来检验以下假设：施用抗体后 T 细胞会被耗尽加速疾病的解决并允许更快地停止类固醇治疗，而无需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采用低剂量甲氨蝶呤进行治疗，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解决，并允许更快停止类固醇治疗，不会增加复发恶性肿瘤的风险。在目标 3、第一阶段和将进行 II 期临床试验，以检验施用 CD28 特异性抗体的假设正如之前的实验室研究表明的那样，对于治疗或预防急性 GVHD 是有效的。患者目前可用治疗无法控制的 GVHD 将进入 I 期临床审判。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来测试是否施用该抗体可以预防人类的 GVHD。与公共卫生的相关性：该项目的研究可能会导致开发更有效的药物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。成功的开发此类方法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。 '