Spatially Controlled Priming of CAR T Cells in Solid Tumors via Focused Ultrasound

/Abstract CAR T cell therapy has revolutionized the treatment of hematologic cancers, but its application in solid tumors is limited by antigen heterogeneity and off-tumor toxicity. To address this challenge, I propose to engineer a focused ultrasound (FUS)-based gene control system that enables spatially confined T cell priming within the tumor microenvironment. This system, building on my published work in sono-mechanogenetics, will use FUS to activate synthetic gene circuits in tumor cells, leading to localized antigen expression and activation of synNotch CAR T cells. This “training center” approach aims to transform tumors into precise activation zones for CAR T therapy, functionally redefining tumor-associated antigens as safe therapeutic targets. The research plan includes three integrated objectives: (1) optimize ultrasound parameters for safe and robust cellular activation in 3D tumor models, (2) develop and validate synthetic gene circuits with enhanced specificity and dynamic range guided by mechanistic studies, and (3) evaluate therapeutic efficacy and safety in vivo using a breast cancer model. These studies will establish a spatially controllable, noninvasive immunotherapy platform with strong translational potential. My long-term goal is to become an independent investigator developing ultrasound-controlled gene and cell therapies. This K01 award will provide structured training in ultrasound instrumentation, synthetic biology, and cancer immunology, and will support my transition to a faculty position. I will work under the mentorship of Dr. Yingxiao Wang, with co-mentorship from Drs. Qifa Zhou and Bingfei Yu, and consultation from experts in CAR T therapy and tumor modeling. The training environment at USC offers outstanding resources and a collaborative ecosystem to advance my interdisciplinary research and professional development. Project Number: 1K01CA312442-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Chi Woo Yoon | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $137,459 | Activity Code: K01 | Study Section: Special Emphasis Panel[ZRG1 ISB-G (85)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11352873