Immune Modulation After Allogeneic HCT

同种异体 HCT 后的免疫调节

• 批准号: 10628826
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-08-14 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10628826
• 关键词: AML/MDS; Address; Allogenic; Antigens; B-Lymphocytes; Biometry; Cell Communication; Cell Therapy; Cells; Clinical; Clinical Research; Clinical Trials; Clonal Evolution; Development; Disease remission; Dissection; Engineering; Engraftment; Evolution; Failure; Frequencies; Future; Genetic; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Immune; Immune System Diseases; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunogenomics; Immunologics; Integration Host Factors; Intervention; Laboratory Study; Lead; Leukemic Cell; Malignant Neoplasms; Marrow; Minor Histocompatibility Antigens; Outcome; Patient-Focused Outcomes; Patients; Population; Prevention trial; Reaction; Recurrence; Recurrent disease; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Residual Tumors; Residual state; Resistance; Resource Sharing; Sampling; Series; Shapes; Steroids; T-Lymphocyte; Testing; Tissues; Transplant Recipients; Transplantation; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; Vaccination; Vaccine Antigen; Work; base; cellular engineering; checkpoint inhibition; chronic graft versus host disease; clinical trial implementation; combinatorial; curative treatments; demographics; design; donor stem cell; graft vs host disease; hematopoietic cell transplantation; high risk; immune reconstitution; immunomodulatory therapies; immunoregulation; improved; innovation; insight; ipilimumab; neoantigens; neoplastic cell; novel; novel therapeutic intervention; post-transplant; prevent; programs; relapse risk; response; single cell technology; success; synergism; transmission process; treatment trial

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.

节目概要 尽管异基因造血细胞移植（HCT）为许多患有造血干细胞缺乏症的患者提供了治愈性治疗， 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 成功的障碍。这两种障碍都代表了免疫调节的失败。认识不足 新移植的供体免疫系统对残留肿瘤细胞的破坏， 患者的恶性肿瘤，而对宿主抗原的不受控制的反应导致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 组织是改善allo-HCT后患者结局的关键。该计划的总体目标是更深入地 深入了解造成这些失败的捐助者和东道国因素， 免疫学方法来纠正它们。这一目标将通过临床和实验室研究来实现 在3个项目中进行，并得到3个共享资源的支持。项目和核心是高度互动的 并由研究人员领导，他们合作进行了一系列研究， 临床试验，以评估预防高风险移植受者复发的新策略，治疗复发 在移植后的患者中，以及治疗难治性慢性GVHD。预防试验包括检查点 伊匹单抗抑制，工程化全细胞疫苗接种，以及个性化疫苗的开发 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 检查点抑制剂与工程细胞疗法联合治疗HCT后复发的患者。试验 慢性GVHD将测试Treg扩增和B细胞调节之间协同作用的发展。解剖 白血病细胞和周围免疫细胞的进化将为我们理解肿瘤逃避提供信息， 机制以及如何克服它们。为此，《方案》着手确定预测指标， AML/MDS的反应或耐药机制，以确定组成和功能的变化， 状态的骨髓浸润免疫细胞，并跟踪演变抗原-T细胞相互作用与 对移植后免疫调节的反应。此外，进一步了解供体来源的克隆 造血塑造造血和免疫重建影响临床结果将创造 新的相互作用，可能适用于未来的干预措施，导致新的治疗药物的开发 战略布局这些努力将为理解免疫系统的机制提供重要的见解。 调节异常以及它们如何导致HCT后复发和慢性GVHD以及创造新的干预措施 克服这些障碍来治愈。