- Remote-controlled mechanogenetics system can be used to engineer Chimeric Antigen Receptor (CAR)-expressing T cells.
- CAR T-cell therapy is a type of immunotherapy where the T-cells (a type of white cells) of the immune system (body defense system against disease) are genetically modified to target and kill cancer cells.
An ultrasound-based system can non-invasively and remotely control genetic processes in live immune T cells so that they recognize and kill cancer cells.
In animals and humans, there is a critical need to non-invasively and remotely manipulate cells at a distance, particularly for translational applications.
The team developed an innovative approach to use mechanogenetics--a field of 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. The research team used ultrasound to mechanically perturb T cells and then converted the mechanical signals into the genetic control of cells.
Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy where the T-cells (a type of white cells) of the immune system (body defense system against disease) are genetically modified in the laboratory. These engineered T-cells are capable of expressing certain receptors on their surface by means of which they are able to recognize specific proteins (antigens or targets) on tumor cells in order to destroy them.
CAR T-cell therapy is a form of adoptive cell transfer treatment since it enhances the activity of T-cells to target and attack cancer cells.
In this study, the research team shows how their remote-controlled mechanogenetics system can be used to engineer chimeric antigen receptor (CAR)-expressing T cells that can target and kill cancer cells. The engineered CAR-T cells have mechano-sensors and genetic transducing modules that can be remotely activated by ultrasound via microbubble amplification.
"CAR-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. This work could ultimately lead to an unprecedented precision and efficiency in CAR-T cell immunotherapy against solid tumors, while minimizing off-tumor toxicities, said bioengineering professor Peter Yingxiao Wang."
The research team 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.
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 chimeric antigen receptor (CAR) for the recognition and killing of target cancer cells.
- Yijia Pan, Ziliang Huang, Molly Allen, Yiqian Wu, Ya-Ju Chang, Shu Chien and Yingxiao Wang, Sangpil Yoon, Changyang Lee, K. Kirk Shung, Jie Sun, Michel Sadelain. 'Mechanogenetics for the remote and non-invasive control of cancer immunotherapy.'Proceedings of the National Academy of Sciences (2017). http:dx.doi.org/10.1073/pnas.1714900115.