SUMMARY This proposal describes a five-year career development program to prepare the candidate, Dr. Jinhwan Kim, for a career as an independent investigator. This program will build on Dr. Kim’s background as a material scientist and nanobiomaterial engineer by providing additional expertise in medical imaging, cell engineering, and nanomaterials. The primary mentor, Stanislav Emelianov, Ph.D. (Professor of BME at Georgia Tech), has expertise in instrumentation, imaging systems and algorithms, image-guided therapy, and imaging contrast agents. Co-mentors are Younan Xia, Ph.D. (Professor of BME at Georgia Tech), who has expertise in nanoparticles and Gabriel Kwong, Ph.D. (Associate Professor of BME at Georgia Tech), whose expertise in T cell engineering. Dr. Kim will collaborate with Kevin Kalinsky, M.D. (Associate Professor of Medicine at Emory University) on breast cancer oncology, Haydn Kissick, Ph.D. (Assistant Professor of Urology at Emory University) on cancer immunology, and Krishnendu Roy, Ph.D. (Professor of BME at Georgia Tech) on T cell manufacturing. In this application, Dr. Kim will demonstrate the use of plasmonic nanoparticles with tunable peak optical absorption as contrast agents for the combined ultrasound and photoacoustic (US/PA) imaging. The developed imaging agents and US/PA system will be used for image-guided chimeric antigen receptor (CAR) T cell therapy in breast cancer and sensing the activity of delivered CAR T cells in the tumor microenvironment (TME). Current approaches in CAR T cell therapy lack the ability to monitor the location and activity of the infused CAR T cells in real-time, which is critical to understand the biological effect of CAR T cells and to predict the treatment outcome. By labeling CAR T cells with gold nanorods (AuNRs) absorbing in near-infrared (NIR) spectral range, this project aims to enable tracking of the CAR T cells after infusion for image-guided therapy (Aim 1). Implementing the US/PA imaging technique will allow the real-time, high-resolution detection of the CAR T cells with great anatomical information in reliable imaging depth (Aim 2). Furthermore, the design of the gold nanoparticle-based US/PA imaging sensors that selectively and sensitively detect cytokines released from injected CAR T cells will enable monitoring CAR T cell activity, thereby assessing and controlling the microenvironment with additional external stimulation (Aim 3). Aims 1 and 2 (K99 phase) will be guided under the strong mentorship from mentor/co-mentors with extensive training on nanotechnology (Younan Xia, Ph.D.), CAR T cell engineering (Gabriel Kwong, Ph.D.), and US/PA imaging (Stanislav Emelianov, Ph.D.). Dr. Kim will independently conduct the proposed aim 3 with the extended expertise gathered during the K99 phase. The multidisciplinary knowledge gained during the overall research and career training, this project will provide a foundation for Dr. Kim – an independent investigator in the R00 phase, to develop advanced applications of nanotechnology in innovative therapeutic approaches to treat cancer and other diseases.

NARRATIVE The limited ability to monitor the infused CAR T cells’ location and activity in real-time contributes to less efficient therapy and more systemic side effects. This proposal seeks to develop an image-guided therapy and activity monitoring/controlling system based on the combination of nanotechnology, combined ultrasound and photoacoustic imaging, and cell engineering to increase treatment precision and decrease side effects.