Controllable solid tumor immunotherapy based on a wireless thermos-activator

Abstract Chimeric Antigen Receptor (CAR) T cell therapy is a groundbreaking treatment for cancer, with the potential to elicit long-lasting immune responses. However, its application in solid tumors is significantly limited by off-tumor toxicities, where normal tissues expressing similar antigens are targeted, leading to lethal side effects (on-target off-tumor toxicity, OTOT). Therefore, there is an urgent need for high-precision control of CAR T cells to confine their activation to local tumor regions. We previously demonstrated the feasibility and safety of using MRI-guided focused ultrasound to precisely control CAR-T cell activation through local hyperthermia. Despite its potential, this approach has notable limitations, including restricted accessibility due to the need for specialized MRI equipment. To overcome these barriers, this project proposes the development of a wearable patch controlled, wireless thermo-activator device that enables precise, localized CAR-T cell activation at tumor sites through controlled heat. The system includes injectable, biodegradable receiver micro-coils, a wearable of a flexible Tx coil and a flexible metasurface. This innovative approach offers remote thermal control, activating thermo- activator CAR-T (TA-CAR) cells with high spatiotemporal precision, providing a convenient, portable, patient- friendly alternative to MRIgFUS. Accordingly, three specific aims are proposed: (1) to develop and optimize wireless injectable thermo-activator device, (2) to test wireless thermo-activator on engineered CAR-T cells for tumor cell killing in vitro, and (3) to evaluate the in vivo therapeutic efficacy of the wireless thermo-activator controllable CAR T cells in solid tumor killing. By providing a flexible, accessible, and repeatable method for CAR-T activation, this technology seeks to enhance the safety and efficacy of cancer immunotherapy. We expect that each component of our approach, wearable controlled thermos-activators, thermo-controllable CARs, will allow opportunities for continuous evolution and adaptation, targeting a broad range of solid tumors and precancerous conditions. This wearable patch controlled therapy offers a groundbreaking advancement in remote-controlled immunotherapy against solid tumors, holding promise in translations to clinical applications.