Immune Modulation After Allogeneic HCT

同种异体 HCT 后的免疫调节

• 批准号: 10701127
• 负责人: Robert Jon Soiffer
• 金额: $ 20万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701127
• 关键词: AML/MDS; Address; Allogenic; Antigens; B-Lymphocytes; Cell Communication; Cell Therapy; Cells; Clinical; Clinical Research; Clinical Trials; Development; Dissection; Engineering; Evolution; Failure; Future; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologics; Integration Host Factors; Intervention; Laboratory Study; Lead; Leukemic Cell; Malignant Neoplasms; Marrow; Minor Histocompatibility Antigens; Outcome; Patient-Focused Outcomes; Patients; Prevention trial; Reaction; Recurrence; Recurrent disease; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Residual Tumors; Residual state; Resistance; Resource Sharing; Series; Shapes; T-Lymphocyte; Testing; Tissues; Transplant Recipients; Tumor Escape; Tumor-infiltrating immune cells; Vaccination; Vaccine Antigen; cellular engineering; checkpoint inhibition; chronic graft versus host disease; combinatorial; curative treatments; design; graft vs host disease; hematopoietic cell transplantation; high risk; immune reconstitution; immunoregulation; improved; innovation; insight; neoantigens; neoplastic cell; novel; novel therapeutic intervention; post-transplant; prevent; programs; response; success; synergism; treatment trial

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.

尽管同种异体造血细胞移植（HCT）为许多患有此病的患者提供了治愈性治疗 血液系统恶性肿瘤、疾病复发和慢性移植物抗宿主病（GVHD）仍然是主要疾病 这两个障碍都代表了免疫调节的失败。 新移植的供体免疫系统对残留肿瘤细胞的破坏使得肿瘤复发 患者的恶性肿瘤，而针对宿主抗原的不受控制的反应会导致 GVHD 增强免疫。 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 后的患者预后至关重要。该计划的总体目标是获得更深入的了解。 深入了解导致这些失败的捐助者和宿主因素，并设计和实施创新 纠正这些问题的免疫学方法将通过临床和实验室研究来实现。 在 3 个项目中进行并由 3 个共享资源支持这些项目和核心具有高度的交互性。 并由研究人员领导，他们合作进行了一系列研究，导致了挑衅性的发展 评估预防高风险移植受者复发、治疗复发的新策略的临床试验 移植后患者的治疗和解决难治性慢性 GVHD 预防试验包括检查点。 使用 ipilumumab 抑制、工程化全细胞疫苗接种以及个性化疫苗开发 新抗原/次要组织相容性抗原疫苗治疗试验包括配对组合策略。 检查点抑制剂与工程细胞疗法治疗 HCT 后复发的患者。 慢性 GVHD 将测试 Treg 扩增和 B 细胞调节之间的协同作用。 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避 为此，该计划着手定义预测因素和解决办法。 AML/MDS 的反应或抵抗机制，以确定成分和功能的变化 骨髓浸润免疫细胞的状态，并跟踪与相关的不断变化的抗原-T细胞相互作用 此外，还进一步了解了供体来源的克隆的情况。 造血作用塑造造血和免疫重建以影响临床结果将创造 新的相互作用可能适合未来的干预措施，从而导致治疗小说的发展 综合起来，这些努力将为理解免疫机制提供重要的见解。 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 解决这些治愈障碍。