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 ...