Ultrasound-Controlled Remote activation of CAR T-cells for localized tumor immunotherapy
Chimeric antigen receptor (CAR) T cells show potential as paradigm-shifting therapeutic agents for cancer
treatment. CAR-T based immunotherapy, however, can have off-target activity against normal cells and cause
life-threatening adverse reactions such as cytokine storms. To mitigate this side effect, we propose to explore
high-precision focused ultrasound as a means to confine CAR T cell activation within solid tumor tissue space.
In the proposed work, we will use ultrasound to deliver energy safely and noninvasively into small volumes of
tissue deep inside the body. We will develop technology and protocols for ultrasound-guided remote-activation
of CAR expression in T-cells, which are clinically compatible and able to convert ultrasound waves into short
pulses of local heat generation. Specifically, we will engineer molecular thermo-sensors (acousto-sensors) into
T-cells along with genetic transducing modules (GTMs), and use focused ultrasound to produce short pulsed
heat to activated CAR therapeutic response for focal targeting on solid tumors. We will incorporate reporters to
provide direct detection of therapeutic responses, and use the information to calibrate and optimize the system.
Therefore, three specific aims are proposed: (1) Develop ultrasound-activatable thermo-sensors and GTMs; (2)
Engineer ultrasound-activatable CAR T-cells; (3) Examine the immunotherapeutic efficacy CAR T-cells against
solid tumors in vivo. Upon success, this first-of-kind research will specifically transduce remote ultrasound
stimulation into genetic expression of T-cells for locally controlled immunotherapy. This approach to solid tumor
immunotherapy is expected to open new opportunities to integrate engineering with medicine, and result in many
successful translations from fundamental science and engineering to applications with clinical utility.