Hypofractionated radiation in combination with B7-H3-CAR T cells for pediatric patients with relapsed/refractory sarcomas - PROJECT SUMMARY/ABSTRACT My overarching career goal as a clinician scientist is to become an independent investigator, who develops novel cellular immune therapies to improve outcomes for pediatric patients with high-risk malignancies. This K08 application proposes a career development plan and research strategy that are structured to provide the focused mentorship, dedicated coursework, hands-on training, and protected time that will be necessary for me to successfully transition into an independent leadership role. My research plan addresses the unmet need that pediatric patients with relapsed/refractory (r/r) sarcomas have dismal outcomes with current approaches, and initial attempts to translate cellular immunotherapy for this population have been limited by the hostile tumor microenvironment. My proposal centers on the hypothesis that priming with hypofractionated radiation therapy (HFRT) will modulate the local and systemic tumor environment, improving the antitumor activity of B7-H3-CAR T cells. To interrogate this hypothesis, I will implement a phase I clinical trial evaluating the safety and antitumor activity of B7-H3-CAR T cells post HFRT and lymphodepleting chemotherapy in pediatric patients with r/r sarcomas (Aim 1). I will oversee the conduct and interpretation of embedded correlative studies, together with laboratory-based collaborators, seeking to assess the in vivo expansion, persistence, and functional state of B7-H3-CAR T cells and elucidate mechanisms of immune escape (Aim 2). Importantly, while these aims focus on pediatric patients with r/r sarcomas, B7-H3-targeted therapy has the potential for application in a range of pediatric and adult malignancies. The proposed correlative studies will produce generalizable knowledge about the interaction between radiation and the immune environment informing broad combination immune therapy efforts. I have developed a scholarly oversight committee composed of senior investigators who are leaders in their respective disciplines, possess diverse technical expertise, and have track records of successful research, mentorship, and funding support. Together with my mentors and advisors, I have crafted a career development plan focused on the goals of i) gaining an oncology perspective in multimodal treatment strategies for pediatric solid tumors, ii) applying advanced techniques in biostatistics and early-phase clinical trial design, iii) designing and interpreting robust immunologic correlative studies, and iv) cultivating leadership skills. The rigorous training provided by this mentored award will prepare me for a career dedicated to translating novel cellular immune therapies for pediatric patients with high-risk malignancies through early- phase clinical trials and integrated correlative studies to enable reverse translation. Upon completion of the K08 award period, I expect to have garnered the necessary training to support my transition to an independent investigator role and generated data that will inform subsequent clinical trial R01 applications supporting future combination cellular therapy efforts for pediatric solid tumors.
