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: 8459330
• 负责人: Rainer F. Storb
• 金额: $ 178.85万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459330
• 关键词: Address; Adverse effects; Age; Allogenic; Allografting; Antigens; Autologous; Biological; Canis familiaris; Cells; Chimerism; Clinical; Collaborations; Comorbidity; Diagnosis; Disease; Foundations; Genomics; Goals; Health Benefit; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Human; Immune; Immunosuppression; Knowledge; Malignant - descriptor; Malignant Neoplasms; Marrow; Minor Histocompatibility Antigens; Modality; Modeling; Non-Malignant; Patients; Public Health; Recording of previous events; Recovery; Regimen; Risk; Safety; Staging; Stem cells; Toxic effect; Translations; Transplant Recipients; cancer cell; conditioning; cytotoxic; graft vs host disease; hematopoietic cell transplantation; improved; leukemia; novel; pre-clinical; prevent; programs; success; tumor

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非清髓性预处理后同种异体造血细胞移植（HCT）在治疗血液恶性肿瘤患者中的应用并提高其成功率和安全性。为此，我们提出了两个临床前项目和两个临床项目。临床前项目 1 和 2 涉及具有悠久临床转化历史的犬 HCT 模型。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 中的三个主要问题。一是用诱导供体移植物耐受的生物方法取代细胞毒性预处理方案，从而减少与后期方案相关的后遗症。另一个目标是探索预防移植物抗宿主病（GVHD）的新方法，以避免目前长期移植后免疫抑制的需要和副作用。第三个目标是改善根除在项目 3 和 4 下移植的患者中所见的持续性恶性肿瘤。第三个目标将使用混合供体/宿主造血嵌合和实验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，研究如何在不冒 GVHD 风险的情况下增强移植物抗肿瘤效应。项目2将使用基因组学方法来鉴定犬次要组织相容性抗原，目的是区分那些仅限于造血细胞表达的抗原和普遍表达的抗原。该项目产生的知识将增加我们对 GVHD 和移植物抗肿瘤效应的理解。项目 3 和 4 使用同种异体 HCT 治疗患有晚期血液恶性肿瘤的人类患者。 HCT 方案使用真正的非清髓性调理，这一点通过那些罕见的排斥移植物的患者的自体骨髓恢复得到证明。它具有最小的早期毒性，重要的是，除了调节之外，还可以最纯粹地测定移植物抗肿瘤效应，并且可以最佳地测定不因治疗方案相关毒性而增强的 GVHD。它为添加疾病和疾病阶段特定模式提供了良好的基础，其中将包括项目 3 中的免疫操作和项目 4 中的药理学操作。该计划的公共卫生益处强调了以下事实：自从临床引入在非清髓性治疗方案中，超过 1,200 名患有各种恶性和非恶性血液疾病的患者从同种异体 HCT 治疗中受益，否则这些患者可能会因年龄和合并症而被排除在外。这一点尤其重要，因为大多数候选疾病患者诊断时的中位年龄为 65 至 70 岁，这超出了传统清髓性 HCT 方案纳入的年龄范围。