Mixed Hematopoietic Chimerism After Stem Cell Allografts

干细胞同种异体移植后的混合造血嵌合

• 批准号: 8067936
• 负责人: Rainer F. Storb
• 金额: $ 190.95万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-30 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067936
• 关键词: Mixed; Hematopoietic; Chimerism; After; Stem

DESCRIPTION (provided by applicant): The goals of this Program are to broaden the application and increase success and safety of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in treating of patients with hematologic malignancies. To this end, we propose two preclinical and two clinical projects. The preclinical Projects 1 and 2 involve a canine model of HCT with a long history of clinical translation. Project 1, which developed the clinical HCT regimen used in Projects 3 and 4, will address three major issues in allogeneic HCT. One is to replace the cytotoxic conditioning regimen with biological means of tolerance induction to donor grafts and thereby reduce late regimen-related sequela. Another is to explore novel ways of preventing graft-vs.-host disease (GVHD) that will avoid the need for and side effects from current long-term post-grafting immunosuppression. The third is to improve eradication of persistent malignancies as seen in patients transplanted under Projects 3 and 4. This third aim will use mixed donor/host hematopoietic chimerism and experimentally-induced leukemia as models of persisting malignant cells and, in collaboration with Project 2, investigate how to enhance graft-vs.-tumor effects without risking GVHD. Project 2 will use genomics approaches to identify canine minor histocompatibility antigens with the goal of discriminating between those antigens whose expression is restricted to hematopoietic cells and those which are ubiquitously expressed. Knowledge generated in this project will increase our understanding of GVHD and graft-vs.-tumor effects. Projects 3 and 4 use allogeneic HCT to treat human patients with advanced hematologic malignancies. The HCT regimen uses truly nonmyeloablative conditioning as evidenced by autologous marrow recovery in those rare patients who reject their grafts. It has minimal early toxicities and, importantly, allows for the purest determination of graft-vs.-tumor effects apart from conditioning and the best determination of GVHD not augmented by regimen-related toxicities. It provides an excellent foundation on which to add disease and disease stage specific modalities, which will include immune manipulations in Project 3 and pharmacological manipulations in Project 4.The public health benefits of the Program are underscored by the fact that, since the clinical introduction of the nonmyeloablative regimen, more than 1,200 patients with various malignant and nonmalignant blood disorders have benefited from treatment by allogeneic HCT who otherwise would have been excluded because of age and co-morbidities. This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens.

描述（由申请人提供）：该计划的目标是扩大应用程序，并在非甲状腺造血条件治疗血液系统恶性肿瘤患者方面的同种异体造血细胞移植（HCT）的成功和安全性。为此，我们提出了两个临床前和两个临床项目。临床前项目1和2涉及HCT犬模型，具有较长的临床翻译历史。项目1开发了项目3和4中使用的临床HCT方案，将解决同种异体HCT的三个主要问题。一种是用对供体移植物的耐受性诱导耐受性的生物学手段代替细胞毒性调节方案，从而减少晚期与治疗方案相关的后遗症。另一个是探索预防移植物疾病（GVHD）的新型方法，这些方法将避免当前长期治疗后免疫抑制的需求和副作用。第三个是在项目3和4下移植的患者中改善对持续性恶性肿瘤的根除。第三个目标将使用混合的供体/宿主造血嵌合体和实验性诱导的白血病作为持续性恶性细胞的模型，并与项目2合作时，调查了如何增强Graft-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-vs.-tign-vs.-timps gvh offing gvh。项目2将使用基因组学方法来识别犬较小的组织相容性抗原，其目的是区分那些表达的抗原，其表达仅限于造血细胞以及普遍表达的抗原。该项目中产生的知识将增加我们对GVHD和GRAFT-VSS肿瘤效应的理解。项目3和4使用同种异体HCT治疗患有晚期血液学恶性肿瘤的人类患者。 HCT方案采用了真正的非甲状腺素调节，这是拒绝其移植物的罕见患者的自体骨髓恢复的证明。它具有最低的早期毒性，重要的是，除了条件和最佳的GVHD测定外，还允许最纯粹确定移植物效应，而与治疗相关毒性的最佳测定也无法增强。它为添加疾病和疾病阶段特定方式的良好基础提供了良好的基础，该模式将包括项目3中的免疫操作和项目4中的药理学操纵。和合并症。这一点尤其重要，因为大多数候选疾病患者诊断的中位年龄在65至70岁之间，这超出了常规髓质性HCT方案的年龄范围。