Immune Modulation After Allogeneic HCT

计划摘要 虽然异基因造血细胞移植(HCT)为许多慢性粒细胞白血病患者提供了根治性治疗。 恶性血液病、疾病复发和慢性移植物抗宿主病(GVHD)仍然是主要的 阻碍成功的因素。这两个障碍都代表了免疫调节的失败。认识不足 通过新植入的供者免疫系统破坏残留的肿瘤细胞，可以使AFP复发 患者的恶性，而对宿主抗原的不受控制的反应导致移植物抗宿主病。增强免疫力 针对残留白血病细胞的反应，同时控制针对正常宿主的反应 组织对于改善allo-HCT后患者的预后至关重要。该计划的总体目标是更深入地了解 洞察造成这些失败的捐赠者和东道国因素，并设计和实施创新 用免疫学的方法来纠正它们。这一目标将通过临床和实验室研究来实现 在3个项目中执行，并由3个共享资源提供支持。项目和核心具有很强的互动性 并由调查人员领导，他们合作进行了一系列研究，导致了挑衅性 评估预防高危移植受者复发、治疗复发的新策略的临床试验 在移植后的患者中，以及处理难治性慢性移植物抗宿主病。预防试验包括检查站 使用ipilumab抑制，工程全细胞疫苗接种，并开发个性化 新抗原/次要组织相容性抗原疫苗。治疗试验包括组合策略配对 检查点抑制剂和工程细胞疗法用于治疗HCT后复发的患者。在中国进行试验 慢性GVHD将测试Treg扩增和B细胞调节之间的协同作用的发展。剖析 白血病细胞和周围免疫细胞的进化将有助于我们理解肿瘤逃逸 机制以及如何克服这些机制。为此，该方案着手定义预测因素和 AML/MDS的应答或耐药机制，以确定其组成和功能的变化 骨髓浸润性免疫细胞的状态，并跟踪与以下相关的不断演变的抗原-T细胞相互作用 对移植后免疫调节的反应。此外，进一步了解供体是如何获得克隆的 影响临床结果的造血和免疫重建将形成造血和免疫重建 新的相互作用可能服从于未来的干预措施，导致新的治疗方法的开发 战略。综上所述，这些努力将为理解免疫机制提供关键的见解 调节失调及其如何导致HCT后复发和慢性GVHD以及创造新的干预措施 解决这些障碍来治愈。

Program Summary Although allogeneic hematopoietic cell transplantation (HCT) provides curative therapy for many patients with hematologic malignancies, disease relapse and chronic graft versus-host-disease (GVHD) continue to be major impediments to success. Both of these obstacles represent failures of immune regulation. Inadequate recognition and destruction of residual tumor cells by a newly engrafted donor immune system permit recurrence of a patient’s malignancy, while uncontrolled reactions against host antigens lead to GVHD. Enhancing immune responses directed against residual leukemia cells while controlling responses directed against normal host tissues is critical to improving patient outcomes after allo-HCT. The overall goal of this Program is to gain deeper insight into donor and host factors that contribute to these failures and to design and implement innovative immunologic approaches to correct them. This goal will be accomplished through clinical and laboratory studies carried out in 3 Projects and supported by 3 Shared Resources. The projects and cores are highly interactive and led by investigators who have collaborated in a series of studies leading to the development of provocative clinical trials to evaluate new strategies for preventing relapse in high risk transplant recipients, treating relapse in patients post-transplant, and tackling refractory chronic GVHD. Prevention trials include include checkpoint inhibition with ipilumumab, engineered whole cell vaccination, and development of personalized neoantigen/minor histocompatibility antigen vaccines. Treatment trials include combinatorial strategies pairing checkpoint inhibitors with engineered cellular therapy to treat patients who have relapsed post-HCT. Trials in chronic GVHD will test development of synergies between Treg expansion and B cell modulation. Dissection of the evolution of both leukemia cells and surrounding immune cells will inform our understanding of tumor evasion mechanisms and how they might be overcome. To this end, the Program sets out to define predictors and mechanisms of response or resistance of AML/MDS, to determine the changes in the composition and functional state of marrow-infiltrating immune cells, and to track evolving antigen-T cell interactions in association with response to post-transplant immunomodulation. Additionally, further understanding how donor derived clonal hematopoiesis shapes hematopoietic and immunologic reconstitution to influence clinical outcomes will create new interactions that may be amenable to future interventions leading to the development of novel therapeutic strategies. Taken together these efforts will give critical insights into understanding mechanisms of immune dysregulation and how they lead to relapse and chronic GVHD post-HCT as well as creating novel interventions address these obstacles to cure.