Immune Modulation After Allogeneic HCT

同种异体 HCT 后的免疫调节

• 批准号: 10465092
• 负责人: Robert Jon Soiffer
• 金额: $ 268.46万
• 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/10465092
• 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.

程序摘要 尽管同种异性造血细胞移植（HCT）为许多患者提供治疗疗法 血液系统恶性肿瘤，疾病缓解和慢性移植与宿主 - 疾病（GVHD）继续是主要的 成功的障碍。这两个障碍都代表了免疫调节的失败。识别不足 并通过新植入的供体免疫系统破坏残留的肿瘤细胞允许复发 患者的恶性肿瘤，而对宿主抗原的不受控制导致GVHD。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后的患者预后至关重要。该计划的总体目标是更深入 洞悉捐助者和寄宿因素，这些因素会导致这些失败并设计和实施创新 免疫方法纠正它们。该目标将通过临床和实验室研究实现 在3个项目中进行，并得到3个共享资源的支持。这些项目和核心是高度互动的 并由研究人员领导的研究人员在一系列研究中合作，导致了挑衅的发展 临床试验，以评估防止高风险移植受者缓解的新策略，治疗救济 在移植后患者和应对难治性慢性GVHD的患者。预防试验包括检查站 用ipilumumab抑制，设计全细胞疫苗并开发个性化 新抗原/较小的组织兼容性抗原疫苗。治疗试验包括配对组合策略 检查点抑制剂具有工程性细胞疗法，以治疗HCT后转移的患者。试验 慢性GVHD将测试Treg扩展和B细胞调节之间的协同作用。解剖 白血病细胞和周围免疫细胞的演变将告知我们对肿瘤进化的理解 机制及其如何克服。为此，该计划着手定义预测变量和 AML/MDS的响应或抗性机制，以确定组成和功能的变化 骨髓浸入免疫细胞的状态，并跟踪与与 对移植后免疫调节的反应。另外，进一步了解捐助者如何衍生克隆 造血形状造血和免疫机构重建以影响临床结果 可能适合未来干预措施的新互动，从而发展新疗法 策略。综合这些努力将为理解免疫机制提供关键的见解 失调及其如何导致继电器和慢性GVHD后HCT以及创建新颖的干预措施 解决这些治愈的障碍。