The space-age fiction stories and shows of the past depicting nontouch surgery and medical treatments may have arrived. Scientists at the University of California, San Diego have developed a technology to remotely control the activation of CAR-T cells with the goal of noninvasive and specific regulation of CAR-T cells against tumor tissue while sparing surrounding normal tissue. CAR-T cells are powerful weapons against tumors; however, potentially life-threatening toxicity to nontarget cells can be a limiting factor in the widespread clinical application of CAR-T in the short term. A means to improve the accuracy of tumor-cell targeting would enhance the clinical utility of CAR-T immunotherapy.
The new research involves the use of ultrasound and microscopic microbubbles as the basis of mechnosensor technology to turn on the genes of CAR-T cells. This approach of using mechanosensors to influence gene expression (mechanogenetics) involves the binding of streptavidin-coated microbubbles (between 1 µm and 1 mm in diameter) to the cell surface at the location of Piezo 1 mechanically-activated ion channels. Ultrasound waves were used to cause vibration of the microbubbles, and this vibration causes the Piezo 1 channels to open allowing the influx of calcium ions into the cell. This influx leads to cell signals that activate CAR mediated by engineered genetic transducing modules.
The successful activation of the Piezo 1 ion channels was observed, and flow cytometry methods with T cells verified the mechanogenetic activation of CAR. Peripheral blood mononuclear cells (PBMCs) have high expression of Piezo 1 and were transfected with anti-CD19 CAR and mixed with test target B-cell leukemia cells expressing CD19 antigen. The ultrasound-induced PBMCs with remote-controlled mechanogenetics caused more death to the test leukemia B cells than the PBMCs not exposed to ultrasound or those without the remote-controlled mechanogenetics although exposed to ultrasound.
The ability to precisely control the expression of CAR to specifically destroy tumor cells will change the face of anti-cancer immunotherapy and increase its utility by reducing toxicity. The remote-control method is also noninvasive, further enhancing treatment safety. This technology has the potential for use in other types of therapeutics where precise spatiotemporal gene control is paramount.
Pan, Y., Yoon, S., Sun, J., Huang, Z., Lee, C., & Allen, M. et al. (2018). Mechanogenetics for the remote and noninvasive control of cancer immunotherapy. Proceedings Of The National Academy Of Sciences, 115(5), 992-997. doi:10.1073/pnas.1714900115