PROJECT SUMMARY/ABSTRACT Quaovi Sodji, MD, PhD is a Tenure track Assistant Professor in the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health in Madison. His long-term goal is to use his acquired clinical and research expertise in radiation oncology, drug discovery and cancer immunotherapy to develop treatments that can improve the lives of patients with solid tumors including the pediatric cancer neuroblastoma. He aims to develop a translational research program investigating the use of low-dose targeted radionuclide therapy (TRT) to sensitize tumors to killing by chimeric antigen receptor (CAR) T cells. The purpose of this career development award is to provide Dr. Sodji with the support and mentorship needed to develop a successful translational research program. His proposal will be performed under the primary mentorship of Zachary Morris, MD, PhD, an expert in immuno-radiobiology and Christian Capitini, MD, an expert in CAR T cell therapy. Other members of his mentorship committee include Paul Sondel, MD, PhD, an expert in immunogenetics, Jamey Weichert, PhD, an expert in radionuclide chemistry and Bryan Bednarz PhD, an expert in nuclear medicine. The training plan includes formal coursework, seminars, national conferences, and hands- on training activities to expand expertise in 1) tumor immunology and CAR T cell engineering, 2) radiochemistry and dosimetry, and 3) laboratory management, mentoring, and grantsmanship. CAR T cells are “living drugs”, tailored to each patient that can directly recognize and kill cancer cells. They have been very effective against blood cancers, but not against solid tumors including one of the most common childhood cancers, neuroblastoma, which is very deadly cancer when it relapses. This limitation of CAR T cells in solid tumors has been attributed to their inability to penetrate the tumors and the loss of their killing potential over time. TRT, a form of radiation where a radioactive chemical is linked to a drug that can selectively deliver it to cancer cells, has been shown to increase the infiltration of immune cells into tumors and the susceptibility of tumor cells to immune-mediated destruction. The goal of this proposal is to use TRT to deliver radiation to all tumors throughout the body to overcome the factors that presently limit the success of CAR T cells against solid tumors like neuroblastoma. This proposal aims to 1) identify the amount of TRT-emitted radiation that CAR T cells can safely withstand, 2) determine if and how this form of radiation increases the potential of CAR T cells to kill tumor cells and 3) evaluate whether TRT in combination with CAR T cells is effective in eradicating tumors in murine models of neuroblastoma. This proposal will lay the groundwork to justify the evaluation of this combination therapy in clinical trials for patients with neuroblastoma. Our anticipated findings will have enormous translational potential as a ther...