Optimizing outcomes for children and young adults with relapse of B-cell acute lymphoblastic leukemia after CD19-targeted chimeric antigen receptor T-cell therapy

优化 CD19 靶向嵌合抗原受体 T 细胞治疗后 B 细胞急性淋巴细胞白血病复发的儿童和年轻人的结局

• 批准号: 10572071
• 负责人: Regina M Myers
• 金额: $ 18万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572071
• 关键词: Adult; Antigen Targeting; Award; B-Cell Acute Lymphoblastic Leukemia; Biological Markers; CAR T cell therapy; CD19 Antigens; CD19 gene; Cell Therapy; Child; Childhood; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Cytotoxic agent; Data; Disease remission; Disease-Free Survival; Enrollment; Environment; Epidemiologic Methods; Epidemiology; Failure; Foundations; Frequencies; Goals; Hematologic Neoplasms; Immune; Immunotherapy; Infrastructure; Instruction; International; Investigational Therapies; K-Series Research Career Programs; Lead; Malignant Childhood Neoplasm; Mediating; Mentorship; Methodology; Methods; Mus; Outcome; Outcomes Research; Patients; Pediatric Hospitals; Pediatric Oncology; Pediatrics; Pennsylvania; Phase; Phase I/II Clinical Trial; Philadelphia; Physicians; Predictive Value; Process Assessment; Prognosis; Proxy; Recommendation; Refractory; Relapse; Research; Research Infrastructure; Residual Neoplasm; Resources; Safety; Scientist; Testing; Therapeutic; Time; Toxic effect; Training; Transplant Recipients; Universities; Variant; arm; cancer clinical trial; cancer immunotherapy; career; chemotherapy; chimeric antigen receptor T cells; clinical epidemiology; cohort; comparative effectiveness; comparative effectiveness study; compare effectiveness; conventional therapy; data pipeline; data resource; design; early phase clinical trial; effective therapy; efficacy outcomes; epidemiology study; evidence base; experience; hematopoietic cell transplantation; high risk; immunotherapy clinical trials; improved; improved outcome; innovation; instructor; leukemia; multidisciplinary; next generation; next generation sequencing; novel; novel strategies; novel therapeutics; patient prognosis; phase 1 study; phase I trial; programs; randomized, clinical trials; response; safety outcomes; secondary analysis; specific biomarkers; targeted treatment; treatment strategy; young adult

PROJECT SUMMARY/ABSTRACT This K08 Award encompasses a research and training plan to facilitate Dr. Regina Myers' transition to an independent clinical investigator. Dr. Myers is currently an Instructor of Pediatrics and a pediatric oncology and cell therapy physician at Children's Hospital of Philadelphia and the University of Pennsylvania. Her long-term goal is to develop an independent research program that will integrate early phase clinical trials with advanced epidemiology methodologies in order to improve outcomes for children and young adults with high-risk hematologic malignancies. The training objectives for this award will bridge her prior experience in immunotherapy and outcomes research to her long-term goals, and include: acquiring independence in the design and implementation of early phase immunotherapy clinical trials, expanding her expertise in clinical epidemiology to include advanced methods for causal inference, establishing proficiency in the assessment of clinical trial correlative endpoints, and gaining experience with the application of synthetic control arms in pediatric cancer clinical trials. The proposed activities will be conducted in the resource-rich environment at CHOP/Penn and under the mentorship of an expert, multidisciplinary team led by Dr. Stephan Grupp, an international leader in cancer immunotherapy. CD19-specific chimeric antigen receptor-modified T cells (CAR19) have demonstrated unprecedented responses in relapsed or refractory B-cell acute lymphoblastic leukemia. Unfortunately, however, 50% of children and young adults relapse suffer a subsequent relapse and their prognosis after post-CAR19 relapse is dismal. As the use of CAR19 broadens, there is a corresponding increase in the number of patients with post-CAR19 relapse, creating a critical need to identify optimal salvage treatment approaches. The proposed research aims to improve outcomes after post-CAR19 relapse using novel and complementary clinical research approaches. In Aim 1, Dr. Myers will perform a phase 1/2 clinical trial to test a dual-antigen targeted CAR designed to overcome the primary mechanisms of CAR failure in children with post-CAR19 relapse. Secondary analyses will evaluate the predictive value of specific biomarkers for CAR failure and will compare the dual-targeted CAR against synthetic external control data. In Aim 2, Dr. Myers will assess the comparative effectiveness of existing treatment approaches for post-CAR19 relapse using randomized clinical trial emulation methods, leveraging clinical trial and real-world data from the largest, single-center pediatric CAR cohort. Successful completion of this career development award will advance the field through the introduction of a novel, dual-antigen targeted CAR and the establishment of a robust clinical research infrastructure capable of integrating real-world data with clinical trial data to determine optimal existing treatment strategies and efficiently assess new therapies as they become available. The proposed studies and training plan will provide an outstanding foundation for Dr. Myers' career as a physician-scientist.

项目概要/摘要 该 K08 奖包括一项研究和培训计划，以促进雷吉娜·迈尔斯 (Regina Myers) 博士过渡到 独立的临床研究者。迈尔斯博士目前是一名儿科和儿科肿瘤学讲师 费城儿童医院和宾夕法尼亚大学的细胞治疗医生。她的长期 目标是开发一个独立的研究计划，将早期临床试验与先进的临床试验相结合 流行病学方法，以改善高危儿童和年轻人的结果 血液系统恶性肿瘤。该奖项的培训目标将弥补她之前的经验 免疫疗法和结果研究以实现她的长期目标，包括：获得独立性 设计和实施早期免疫治疗临床试验，扩展了她在临床方面的专业知识 流行病学包括因果推断的先进方法，建立评估能力 临床试验相关终点，并获得合成对照臂应用的经验 儿科癌症临床试验。拟议的活动将在资源丰富的环境中进行 CHOP/Penn 并在 Stephan Grupp 博士领导的多学科专家团队的指导下， 癌症免疫疗法的国际领导者。 CD19特异性嵌合抗原受体修饰T细胞（CAR19）已被证明是前所未有的 复发性或难治性 B 细胞急性淋巴细胞白血病的反应。然而不幸的是，50%的儿童 年轻人的复发会导致随后的复发，并且 CAR19 复发后的预后很差。 随着CAR19的使用范围扩大，CAR19后的患者数量也相应增加 复发，迫切需要确定最佳的挽救治疗方法。拟议的研究目标 使用新颖且互补的临床研究方法改善 CAR19 复发后的结果。 在目标 1 中，Myers 博士将进行 1/2 期临床试验，以测试双抗原靶向 CAR，旨在 克服 CAR19 后复发儿童 CAR 失败的主要机制。二次分析将 评估特定生物标志物对 CAR 失败的预测价值，并将比较双靶点 CAR 针对合成的外部控制数据。在目标 2 中，迈尔斯博士将评估现有技术的比较有效性 使用随机临床试验模拟方法治疗 CAR19 后复发的治疗方法，利用 来自最大的单中心儿科 CAR 队列的临床试验和真实世界数据。 成功完成该职业发展奖将通过引入一个 新型双抗原靶向 CAR 以及建立强大的临床研究基础设施 将真实世界数据与临床试验数据相结合，以有效地确定现有的最佳治疗策略 当新疗法可用时对其进行评估。拟议的研究和培训计划将提供 为迈尔斯博士作为医师科学家的职业生涯奠定了杰出的基础。