We’re a long way from controlling our immune systems as easily as we might change the channels on our televisions, but a new remote-control system, in the hands of clinicians, could enable the narrowcasting of immunotherapies. For example, cancer immunotherapies could be “switched on” in solid tumors and “switched off” in healthy tissues. The new remote-control system, then, could avoid the toxicities associated with the broadcasting of cancer immunotherapy throughout the body.
Like the first television remote controls, the new immunotherapy remote-control system incorporates ultrasound technology. Instead of channel surfing, however, the new system activates chimeric antigen receptor (CAR) T cells, which are engineered to target and kill cancer cells.
Details of the new system are appearing this week in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled “Mechanogenetics for the Remote and Non-Invasive Control of Cancer Immunotherapy.” The article describes engineered CAR T cells that have mechanosensors and genetic transducing modules that can be remotely activated by ultrasound via microbubble amplification.
“[We] have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities,” wrote the article’s authors. “We have further engineered the Jurkat T-cell line and primary T cells (peripheral blood mononuclear cells) to remotely sense the ultrasound wave and transduce it into transcriptional activation for the CAR expression to recognize and eradicate target tumor cells.”
This feat of mechanogenetics was achieved by scientists based at the University of California, San Diego (UCSD). The scientists found that microbubbles conjugated to streptavidin can be coupled to the surface of a cell, where mechanosensitive Piezo1 ion channels are expressed. Upon exposure to ultrasound waves, microbubbles vibrate and mechanically stimulate Piezo1 ion channels to let calcium ions inside the cell.
The influx of calcium ions triggers downstream pathways, including calcineurin activation and NFAT, or nuclear factor of activated T cells, dephoshorylation and translocation into the nucleus. The nucleus-translocated NFAT can bind to upstream response elements of genetic transducing modules to initiate gene expression of CAR T cells for the recognition and killing of target cancer cells.
“CAR T-cell therapy is becoming a paradigm-shifting therapeutic approach for cancer treatment,” said Peter Yingxiao Wang, Ph.D., a corresponding author of the current study and a bioengineering professor at UCSD. “However, major challenges remain before CAR-based immunotherapy can become widely adopted.
“For instance, the nonspecific targeting of CAR T cells against nonmalignant tissues can be life-threatening. This work could ultimately lead to an unprecedented precision and efficiency in CAR T-cell immunotherapy against solid tumors, while minimizing off-tumor toxicities.”
Mechanogenetics—the use of physical forces and changes in the mechanical properties of cells and tissues to influence gene expression—was limited to enabling a narrowcasting functionality among cultured cells. It could, however, be built into more ambitious systems.
“This mechanogenetics approach can be extended to remotely control, in principle, any gene activity in live cells for the reprogramming of cellular functions,” explained the authors of the PNAS article. “The method should also provide a general approach to remotely control molecular functions for biological studies and clinical applications, particularly cell-based cancer immunotherapy.”