Engineering a molecular control switch into immune cells could improve their therapeutic potential. Scientists from Caltech have shown that putting an RNA-based toggle mechanism into both live mice and human T cells allows them to turn cell growth on and off with a specific drug. The researchers ultimately hope to implement the technology in T cell therapeutics, which are currently in clinical testing for treating cancer and other diseases.
“This system gives us the ability to control the fate and function of cell-based therapies,” says Michael Jensen, director of the pediatric cancer program at the City of Hope, a research and treatment center in Duarte, CA, and an author of the paper.
Scientists have long hoped to harness the power of the immune system to kill cancer cells, which can evade immune detection. One approach is to isolate T cells–a type of white blood cell that helps tailor the body’s response to specific pathogens–from a patient’s blood, multiply them, and then inject them back into the patient. Thanks to advances in genetic engineering and gene therapy, researchers are now modifying the isolated cells to better attack cancer. For example, a number of therapies now being tested in patients use T cells engineered to carry a molecule that allows them to selectively bind to cancer cells.
These treatments have shown some success. One problem, however, is that unlike natural T cells, the engineered versions fail to multiply and don’t persist in the bloodstream for long. That limits the cells’ ability to recruit other parts of the immune system to kill the cancer. Giving patients an immune booster called interleukin 2 increases T cell survival and proliferation. However, the treatment is tough on patients–it requires chemotherapy and radiation to wipe out the natural T cells, enhancing the interaction between immune molecules and the modified cells.
Christina Smolke, a bioengineer at Stanford University, and her collaborators are taking a different tack. In 2007, Smolke developed an RNA-based “on-off switch” using the principles of synthetic biology, an offshoot of genetic engineering in which scientists create functioning biological “parts” from molecular components. The device is designed to turn on expression of a certain gene in response to a chemical. In the new study, Smolke’s team put the switch into T cells, creating a mechanism to control the cells.
The toggle switch has an RNA sensor that responds to the asthma drug theophylline, triggering production of an immune molecule that is crucial for T cell proliferation. The researchers injected T cells containing the construct into animals and then fed them theophylline, demonstrating that the modified T cells only prospered when the animals were given the drug. The switch was also effective in human cells. “We harvested T cells from humans, and when we put the constructs into the cells, we get the same control over gene expression and downstream proliferation,” says Smolke, who was named one of TR’s young innovators of the year in 2002. The new research was published this week in the Proceedings of the National Academy of Sciences.