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

项目总结/摘要 这个K 08奖包括一个研究和培训计划，以促进里贾纳迈尔斯博士的过渡到一个 独立临床研究者。迈尔斯博士目前是儿科和儿科肿瘤学讲师， 他是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，将整合早期临床试验与先进的 流行病学方法，以改善高风险儿童和年轻人的结果 血液恶性肿瘤该奖项的培训目标将连接她以前的经验， 免疫治疗和成果研究，她的长期目标，包括：获得独立的 设计和实施早期免疫治疗临床试验，扩大她在临床方面的专业知识 流行病学，包括因果推理的先进方法，建立在评估的熟练程度， 临床试验相关终点，并获得应用合成对照组的经验， 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博士领导的专家多学科团队的指导下， 癌症免疫治疗的国际领导者。 CD 19特异性嵌合抗原受体修饰的T细胞（CAR 19）已经表现出前所未有的 复发性或难治性B细胞急性淋巴细胞白血病的缓解。不幸的是，50%的儿童 并且年轻的成年人复发遭受随后的复发，并且他们在CAR 19后复发后的预后是令人沮丧的。 随着CAR 19的使用范围扩大，CAR 19后的患者数量相应增加。 复发，迫切需要确定最佳挽救治疗方法。拟议的研究目标 使用新的和互补的临床研究方法改善CAR 19后复发的结果。 在目标1中，Myers博士将进行1/2期临床试验，以测试一种双抗原靶向CAR， 克服CAR 19后复发儿童中CAR失败的主要机制。次要分析将 评估特异性生物标志物对CAR失败的预测价值，并将比较双靶向CAR 与合成的外部控制数据进行对比。在目标2中，迈尔斯博士将评估现有的 使用随机临床试验模拟方法的CAR 19后复发治疗方法， 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。 成功完成这项职业发展奖将通过引入一个 新的，双抗原靶向CAR和建立一个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，以确定最佳的现有治疗策略， 评估新的治疗方法。拟议的研究和培训计划将提供一个 为迈尔斯博士作为一名医生和科学家的职业生涯奠定了杰出的基础。

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.