Source: University of California – San Diego
Summary: A team of researchers has developed an ultrasound-based system that can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.
CAR-T therapy (Chimeric Antigen Receptor T-cell therapy) is becoming a paradigm-shifting therapeutic approach for cancer treatment. However, major challenges remain before CAR-based immunotherapy can become widely adopted. For instance, the non-specific targeting of CAR-T cells against nonmalignant tissues can be life-threatening. There is a critical need to non-invasively and remotely manipulate cells at a distance, particularly for translational applications in animals and humans. A research team from the University of California – San Diego developed an innovative approach to use mechanogenetics (a science that focuses on how physical forces and changes in the mechanical properties of cells and tissues influence gene expression) for the remote control of gene and cell activations. They used ultrasound to mechanically perturb T cells and then converted the mechanical signals into genetic control of cells. The research findings were published in the journal Proceedings of the National Academy of Sciences.
In this study, research team shows how their remote-controlled mechanogenetics system can be used to engineer CAR-expressing T cells that can target and kill cancer cells. The engineered CAR-T with mechano-sensors and genetic transducing modules that can be remotely activated by ultrasound through microbubble amplification. They found that microbubbles conjugated to streptavidin (tetrameric protein) 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. This triggers downstream pathways, including calcineurin activation, NFAT dephosphorylation 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 for the recognizing and killing the target cancer cells.
Prof. Peter Yingxiao Wang said, “This work could ultimately lead to an unprecedented precision and efficiency in CAR-T cell immunotherapy against solid tumors, while minimizing off-tumor toxicities.”
More Information: Yijia Pan et al, “Mechanogenetics for the remote and noninvasive control of cancer immunotherapy,” PNAS (2018).