Mixed Hematopoietic Chimerism After Stem Cell Allografts

描述（由申请人提供）：本项目的目标是扩大非清髓后异基因造血细胞移植（HCT）在治疗血液系统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涉及具有长期临床翻译历史的犬类HCT模型。项目1开发了用于项目3和项目4的临床HCT方案，将解决同种异体HCT的三个主要问题。一种是用诱导供体移植物耐受的生物方法取代细胞毒性调节方案，从而减少与方案相关的晚期后遗症。另一个是探索防止贪污的新方法。-宿主病（GVHD）将避免目前移植后长期免疫抑制的需要和副作用。第三是改善在项目3和项目4下移植的患者中所见的持续性恶性肿瘤的根除。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恶性细胞的模型，并与项目2合作，研究如何增强移植物vs。-肿瘤效应而不冒GVHD风险。项目2将使用基因组学方法鉴定犬次要组织相容性抗原，目的是区分那些仅在造血细胞中表达的抗原和那些无处不在表达的抗原。在这个项目中产生的知识将增加我们对GVHD和graft-vs的理解。肿瘤的效果。项目3和4使用同种异体HCT治疗人类晚期血液系统恶性肿瘤患者。HCT方案使用了真正的非清髓调节，在那些罕见的排斥移植物的患者中，自体骨髓恢复证明了这一点。它具有最小的早期毒性，重要的是，可以最纯粹地确定移植物vs。-除调节外的肿瘤效应，以及不受方案相关毒性增强的GVHD的最佳测定。它为添加疾病和疾病阶段特定模式提供了良好的基础，其中包括项目3中的免疫操作和项目4中的药理学操作。由于非清髓方案的临床应用，1200多名患有各种恶性和非恶性血液疾病的患者受益于同种异体HCT治疗，这些患者本来会因年龄和合病而被排除在外，这一事实突显了该方案的公共卫生效益。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在65至70岁之间，这超出了常规清髓性HCT治疗方案的年龄范围。

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.