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Engineering Better Immune Cells

Scientists use synthetic biology to create drug-controlled T cells.

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.

Engineering immunity: When injected into mice, immune cells modified to carry a molecular “on-off switch” (right) survive and grow much more effectively than animals given normal T cells (left). Red indicates a high concentration of T cells. Researchers want to use the switch to improve cell-based cancer therapies.

“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.

“It does address one of the problems with T cell therapies, which is survival and persistence of these cells,” says Darrel Irvine, a bioengineer at MIT who was not involved in the research. Irvine points out that one concern in enhancing T cells’ growth is the possibility that growth could spin out of control. “But they have an elegant solution,” he says. “Through this drug, they can turn it off.”

Because the switch is made from RNA rather than proteins, it may also avoid another issue with existing modified T cells–triggering an attack from the immune system. “An important feature of their system is that it should not trigger a T cell response against the cells themselves,” says Carl June, a pathologist at the University of Pennsylvania.

In addition to its implications for cancer treatment, the research is a significant step forward for synthetic biology. Most synthetic biology parts are created and tested in microbes, such as the research workhorses yeast and E. coli. But the new study showed this particular part can work in human cells as well.

Another of the switch’s benefits is its modular design. Scientists can swap in different sensor and actuator components, so that different drugs can be used to trigger production of other immune molecules.”We want to make them respond to inert molecules like vitamins, which are inexpensive and easy to use and nontoxic for the patient,” says Jensen.

Smolke’s team is now working on altering the system to work with other FDA-approved drugs, and engineering the switch into T cells with tumor recognition systems. Smolke says clinical testing of the technology is still a ways off–they need to show that the system is safe in animals, and that it can slow tumor growth in animal models of cancer.

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