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.

项目摘要 乔纳森·韦伯斯特（Jonathan Webster）博士是血液学恶性肿瘤肿瘤学助理教授 约翰·霍普金斯大学医学院。他是白血病组的成员，已经完成 约翰·霍普金斯彭博公共卫生学院的临床调查课程科学课程。他的主要 导师理查德·琼斯（Richard Jones）博士是肿瘤学教授和骨髓移植的主任 程序。他的同事拉维·瓦拉丹（Ravi Varadhan）博士是生物统计学和 生物信息学。他的咨询委员会包括博士。 Gojo和Smith，白血病临床试验的教师专家， Luznik博士是基于实验室的同种异体血液或骨髓移植（AlloBMT）和 免疫学。 K08 Award的支持将使Webster博士能够获得其他研究技能，接受 创作出版物的指导，发展赠款并执行他的研究项目。韦伯斯特博士的目标是 成为后AlloBMT疗法的新兴领域的独立研究者和领导者。使用 非甲状化条件（NMAC）以及支持性护理和移植物与宿主的改进 疾病（GVHD）预防，例如移植后环磷有磷酰胺（PTCY） 疾病复发以超过移植相关的死亡率，作为同章后治疗失败的主要原因 用于急性淋巴细胞白血病（ALL）和急性髓样白血病（AML）。两个因素特别有 在自动后复发中的重要作用：移植周围的可测量残留疾病（MRD）和能力 供体T淋巴细胞产生移植物 - 白细胞（GVL）效应。预防性后移植物的使用 靶向疗法减少了高风险白血病的复发，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检查一种更广泛的适用方法 Blinatumomab和flotetuzumab分别为ALL和AML作为ALL和AML。博士 韦伯斯特拥有重要的初步数据，证明了在这种情况下Blinatumomab的安全性和轻松的安全性 PTCY之后，可以使用后移植后维持疗法给予。总体目标 提案是在All和AML的AllOBMT之后减少复发。他将通过：1。执行 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。 在移植后患者中对氟津氏菌进行临床试验，以评估安全性。 3。评估影响 T淋巴细胞激活和扩展T细胞受体的移植后维持疗法 （TCR）多样性，T细胞基因表达和表达靶抗原的细胞的耗竭（CD19和 CD123）。这些研究将为移植后维护的随机试验的发展提供信息 在合作小组一级的治疗。有关后AlloBMT维护疗法有效性的数据 移植周期MRD的患者将为未来的患者选择提供信息，而免疫学相关性可能 揭示反应的生物标志物。