Mixed Hematopoietic Chimerism After Stem Cell Allografts

描述(申请人提供)：该计划的目标是扩大异基因造血细胞移植(HCT)的应用范围，提高非清髓条件下异基因造血细胞移植(HCT)在治疗恶性血液病患者中的成功率和安全性。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涉及具有长期临床翻译历史的犬HCT模型。项目1开发了项目3和4中使用的临床HCT方案，将解决异基因HCT中的三个主要问题。其一是用诱导供者移植物耐受的生物学手段取代细胞毒性调节方案，从而减少晚期方案相关的后遗症。另一个是探索预防移植物抗宿主病(GVHD)的新方法，以避免目前移植后长期免疫抑制的需要和副作用。第三个目标是改善持续性恶性肿瘤的根除，就像在项目3和项目4下移植的患者所看到的那样。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久恶性细胞的模型，并与项目2合作，研究如何在不冒移植物抗肿瘤效应的情况下提高移植物抗肿瘤效果。项目2将使用基因组学方法来识别犬的次要组织相容性抗原，目的是区分那些仅表达于造血细胞的抗原和那些普遍表达的抗原。在这个项目中产生的知识将增加我们对移植物抗肿瘤效应的了解。项目3和4使用同种异体血细胞移植治疗晚期血液恶性肿瘤患者。HCT方案使用真正的非清髓性调节，在那些罕见的排斥移植的患者中，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，除了条件作用外，它允许最纯粹地确定移植物对肿瘤的影响，并允许最佳确定GVHD，而不是与方案相关的毒性。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中的药物操作。自临床引入非清髓性方案以来，已有1200多名患有各种恶性和非恶性血液疾病的患者受益于异基因红细胞移植的治疗，否则这些患者将因年龄和合并疾病而被排除在外，这一事实突显了该计划的公共健康益处。这一点尤其重要，因为大多数候选疾病患者确诊时的中位年龄从65岁到70岁不等，这超出了传统的清髓HCT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.