Mixed Hematopoietic Chimerism After Stem Cell Allografts

描述（由申请人提供）：本项目的目的是扩大非清髓性预处理后异基因造血细胞移植（HCT）在治疗恶性血液病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和两个临床项目。临床前项目1和2涉及具有长期临床转化历史的HCT犬模型。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。一种是用诱导供体移植物耐受的生物学手段取代细胞毒性预处理方案，从而减少晚期方案相关后遗症。另一个是探索新的方法来防止移植物vs。宿主疾病（GVHD），这将避免目前长期移植后免疫抑制的需要和副作用。第三是改善在项目3和4下移植的患者中观察到的持续性恶性肿瘤的根除。第三个目标将使用混合供体/宿主造血嵌合体和实验诱导的白血病作为持续存在的恶性细胞的模型，并与项目2合作，研究如何增强移植物抗肿瘤能力。肿瘤的影响，而不会有GVHD的风险。项目2将使用基因组学方法鉴定犬次要组织相容性抗原，目的是区分仅表达于造血细胞的抗原和普遍表达的抗原。在这个项目中产生的知识将增加我们对GVHD和graft-vs的理解。肿瘤效应项目3和4使用同种异体HCT治疗患有晚期恶性血液病的人类患者。HCT方案使用真正的非清髓性预处理，如在罕见的移植物排斥患者中自体骨髓恢复所证明的。它具有最小的早期毒性，重要的是，它允许最纯粹地确定移植物与除了预处理和GVHD的最佳测定外，肿瘤效应不受方案相关毒性的增强。它提供了一个很好的基础，在此基础上增加疾病和疾病阶段的具体方式，这将包括项目3中的免疫操作和项目4中的药理学操作。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治疗中获益，否则他们将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范围为65至70岁，这超出了常规清髓性HCT方案的入选年龄范围。

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.