Bispecific Antibody Maintenance Therapy after Allogeneic Bone Marrow Transplant

项目摘要 乔纳森·韦伯斯特博士是麻省理工学院恶性血液科肿瘤学助理教授 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 约翰霍普金斯大学布隆伯格公共卫生学院的临床调查科学课程。他的初选 导师理查德·琼斯博士是肿瘤学教授和骨髓移植主任 程序。他的另一位导师拉维·瓦拉丹博士是生物统计和医学研究所肿瘤学教授。 生物信息学。他的顾问委员会包括白血病临床试验的教职专家Gojo博士和Smith博士， 卢兹尼克博士是异基因血液或骨髓移植(AllBMT)的实验室专家， 免疫学。K08奖的支持将使韦伯斯特博士获得更多的研究技能，获得 在撰写出版物、开发赠款和执行他的研究项目方面担任导师。韦伯斯特博士的目标是 成为异基因骨髓移植后治疗这一新兴领域的独立研究人员和领导者。对.的使用 非清髓性调节(NMAC)与支持性护理和移植物抗宿主的改善 疾病(GVHD)的预防，如移植后大剂量环磷酰胺(PTCy)，导致 疾病复发取代移植相关死亡率成为异基因骨髓移植治疗失败的主要原因 用于急性淋巴细胞白血病(ALL)和急性髓系白血病(AML)。有两个因素起到了特别的作用 异基因骨髓移植后复发的重要作用：移植围术期可测量残留病(MRD)，以及 供者T淋巴细胞产生移植物抗白血病(GVL)效应。肾移植术后预防性应用 靶向治疗减少了高危白血病的复发，但大多数患者缺乏靶向突变。在这 应用，韦伯斯特博士建议使用双特异性抗体来检查更广泛适用的方法 在ALL和AML中，blinatumomab和fletuzumab分别作为异基因BMT后的维持治疗。Dr。 韦伯斯特有重要的初步数据证明blinatumomab在这种情况下的安全性和易用性 移植后的维持性治疗可以在PTCy之后进行。这件事的首要目标是 建议减少ALL和AML患者allBMT后的复发。他将通过以下方式实现这一目标：1.开展 Blinatumomab作为移植后维护的临床试验，以评估安全性和无复发生存率。2. 在移植后患者中进行氟替珠单抗的临床试验，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细胞受体活化和扩增的影响 (TCR)多样性、T细胞基因表达和表达靶抗原(CD19和CD19)的细胞耗尽 CD123)。这些研究将为移植后维护的随机试验的发展提供信息 合作小组层面的治疗。有关异基因骨髓移植后维持治疗疗效的数据 移植围术期MRD的患者将为未来的患者选择提供信息，而免疫学相关因素可能 揭示反应的生物标志物。

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.