Bispecific Antibody Maintenance Therapy after Allogeneic Bone Marrow Transplant

同种异体骨髓移植后的双特异性抗体维持治疗

• 批准号: 10572777
• 负责人: Jonathan Allen Webster
• 金额: $ 23.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-17 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572777
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Adoption; Adult; Advisory Committees; Allogeneic Bone Marrow Transplantation; Allogenic; Antibody Therapy; Antigen Targeting; Award; B cell therapy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Bioinformatics; Biometry; Bispecific Antibodies; Blood; Bone Marrow Transplantation; CD19 Antigens; CD19 gene; CD3 Antigens; CD8B1 gene; Cells; Clinical Sciences; Clinical Trials; Coupled; Cyclophosphamide; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Educational Curriculum; Eragrostis; Evaluation; Faculty; Future; Gene Expression; Gene Mutation; Goals; Grant; Hematologic Neoplasms; Homologous Transplantation; IL3RA gene; Immune system; Immunologic Stimulation; Immunologics; Immunology; Immunosuppression; Intervention; Isogenic transplantation; Laboratories; Link; Maintenance; Maintenance Therapy; Measurable; Mediating; Mentors; Mentorship; Mutation; Oncology; Patient Selection; Patients; Phase; Play; Population; Pre-B Acute Lymphoblastic Leukemia; Prophylactic treatment; Public Health Schools; Publications; Recommendation; Recovery; Recurrent disease; Reducing Agents; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Remission Induction; Research; Research Personnel; Research Project Grants; Residual Neoplasm; Role; Safety; Source; Specificity; Supportive care; T-Cell Activation; T-Cell Depletion; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Toxic effect; Transplant Recipients; Transplantation; Treatment Failure; United States; Universities; clinical investigation; conditioning; fighting; graft vs host disease; graft vs leukemia effect; high risk; immune reconstitution; improved; leukemia; leukemia relapse; medical schools; member; mortality; neoplastic cell; novel strategies; novel therapeutics; older patient; post-transplant; prevent; professor; programs; prophylactic; randomized trial; recruit; relapse prevention; relapse risk; response biomarker; safety assessment; skills; targeted agent; targeted treatment; therapy development; transplantation therapy

Project Summary Dr. Jonathan Webster is an Assistant Professor of Oncology in the Division of Hematologic Malignancies at The Johns Hopkins University School of Medicine. He is a member of the Leukemia Group and has completed the Science of Clinical Investigation curriculum at the Johns Hopkins Bloomberg School of Public Health. His primary mentor, Dr. Richard Jones, is a Professor of Oncology and the Director of the Bone Marrow Transplantation Program. His co-mentor, Dr. Ravi Varadhan, is a Professor of Oncology in the Division of Biostatistics and Bioinformatics. His advisory committee includes Drs. Gojo and Smith, faculty experts in leukemia clinical trials, and Dr. Luznik, a laboratory-based expert in allogeneic blood or marrow transplantation (alloBMT) and immunology. Support from the K08 award will enable Dr. Webster to gain additional research skills, receive mentorship in authoring publications, develop grants, and perform his research project. Dr. Webster's goal is to become an independent investigator and leader in the emerging field of post-alloBMT therapies. The use of nonmyeloablative conditioning (NMAC) coupled with improvements in supportive care and graft-versus-host disease (GVHD) prophylaxis, such as high-dose post-transplantation cyclophosphamide (PTCy), have led disease relapse to overtake transplant-related mortality as the major cause of treatment failure following alloBMT for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Two factors play a particularly important role in post-alloBMT relapse: peri-transplant measurable residual disease (MRD), and the ability of donor T lymphocytes to generate a graft-versus-leukemia (GVL) effect. The prophylactic post-transplant use of targeted therapies reduces relapses in high risk leukemias, but most patients lack targetable mutations. In this application, Dr. Webster proposes to examine a more broadly applicable approach using the bispecific antibodies blinatumomab and flotetuzumab as post-alloBMT maintenance therapy in ALL and AML, respectively. Dr. Webster has significant preliminary data demonstrating the safety of blinatumomab in this setting and the ease with which post-transplant maintenance therapies can be given following PTCy. The overarching goal of this proposal is to decrease relapse following alloBMT in ALL and AML. He will achieve this by: 1. Conducting a clinical trial of blinatumomab as post-transplant maintenance to assess safety and relapse-free survival. 2. Conducting a clinical trial of flotetuzumab in post-transplant patients to assess safety. 3. Assessing the impact of post-transplant maintenance therapies on the activation and expansion of T lymphocytes, T cell receptor (TCR) diversity, T cell gene expression, and the depletion of cells expressing the target antigens (CD19 and CD123). These studies will inform the development of randomized trials of post-transplant maintenance therapies at the cooperative group level. Data regarding the efficacy of post-alloBMT maintenance therapies in patients with peri-transplant MRD will inform future patient selection, while the immunologic correlates may reveal biomarkers of response.

项目概要 乔纳森·韦伯斯特 (Jonathan Webster) 博士是该大学血液恶性肿瘤科的肿瘤学助理教授 约翰·霍普金斯大学医学院。他是白血病小组的成员，并已完成 约翰霍普金斯大学彭博公共卫生学院的临床研究科学课程。他的小学 导师理查德·琼斯博士是肿瘤学教授兼骨髓移植主任 程序。他的合作导师 Ravi Varadhan 博士是生物统计学和肿瘤学系的肿瘤学教授 生物信息学。他的顾问委员会包括博士。 Gojo 和 Smith，白血病临床试验方面的专家， Luznik 博士是同种异体血液或骨髓移植 (alloBMT) 领域的实验室专家 免疫学。 K08 奖的支持将使 Webster 博士获得额外的研究技能，获得 在撰写出版物、获得资助和执行研究项目方面提供指导。韦伯斯特博士的目标是 成为异基因骨髓移植后治疗新兴领域的独立研究者和领导者。使用 非清髓性调理（NMAC）加上支持治疗和移植物抗宿主的改善 疾病（GVHD）预防，例如高剂量移植后环磷酰胺（PTCy），已导致 疾病复发超过移植相关死亡率，成为 alloBMT 治疗失败的主要原因 用于急性淋巴细胞白血病（ALL）和急性髓细胞白血病（AML）。有两个因素起着特别重要的作用 alloBMT 复发中的重要作用：移植周围可测量残留病 (MRD) 以及 供体 T 淋巴细胞产生移植物抗白血病 (GVL) 效应。移植后预防性使用 靶向治疗可减少高危白血病的复发，但大多数患者缺乏可靶向的突变。在这个 韦伯斯特博士建议使用双特异性抗体研究更广泛适用的方法 blinatumomab 和 flotetuzumab 分别作为 ALL 和 AML 的 alloBMT 后维持治疗。博士。 韦伯斯特拥有重要的初步数据，证明了 blinatumomab 在这种情况下的安全性和易用性 PTCy 后可进行移植后维持治疗。本次活动的总体目标是 提案旨在减少 ALL 和 AML 患者 alloBMT 后的复发。他将通过以下方式实现这一目标： 1. 开展 blinatumomab 作为移植后维持的临床试验，以评估安全性和无复发生存率。 2. 在移植后患者中进行 flotetuzumab 的临床试验以评估安全性。 3. 评估影响 移植后维持治疗对 T 淋巴细胞、T 细胞受体激活和扩增的影响 (TCR) 多样性、T 细胞基因表达以及表达靶抗原（CD19 和 CD123）。这些研究将为移植后维持随机试验的发展提供信息 合作团体层面的治疗。有关异基因骨髓移植后维持治疗疗效的数据 围移植期 MRD 患者将为未来的患者选择提供信息，而免疫学相关性可能会影响未来的患者选择。 揭示反应的生物标志物。