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‘Rewired’ cells could use custom powers against cancer

Synthetic biologists have developed a general method for “rewiring” immune cells to reverse cancer’s suppression of the immune system.

“Right now, one of the most promising frontiers in cancer treatment is immunotherapy—harnessing the immune system to combat a wide range of cancers,” says lead author Joshua N. Leonard, associate professor of chemical and biological engineering at Northwestern University’s McCormick School of Engineering.

“The simple cell rewiring we’ve done ultimately could help overcome immunosuppression at the tumor site…”

“The simple cell rewiring we’ve done ultimately could help overcome immunosuppression at the tumor site, one of the most intransigent barriers to making progress in this field.”

When cancer is present, molecules secreted at tumor sites render many immune cells inactive. The researchers genetically engineered human immune cells to sense the tumor-derived molecules in the immediate environment and to respond by becoming more active, not less.

This customized function, which is not observed in nature, is clinically attractive and relevant to cancer immunotherapy. The general approach for rewiring cellular input and output functions should be useful in fighting other diseases, not just cancer.

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“This work is motivated by clinical observations, in which we may know why something goes wrong in the body, and how this may be corrected, but we lack the tools to translate those insights into a therapy,” says Leonard, a member of Northwestern’s Robert H. Lurie Comprehensive Cancer Center.

“With the technology we have developed, we can first imagine a cell function we wish existed, and then our approach enables us to build—by design—a cell that carries out that function.”

Currently, scientists and engineers lack the ability to program cells to exhibit all the functions that, from a clinical standpoint, physicians might wish them to exhibit, such as becoming active only when next to a tumor. This study addresses that gap, Leonard says.

Input and output

The study, published in the journal Nature Chemical Biology, provides details of the first synthetic biology technology enabling researchers to rewire how mammalian cells sense and respond to a broad class of physiologically relevant cues.

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Starting with human T cells in culture, the research team genetically engineered changes in the cells’ input and output, including adding a sensing mode, and built a cell that is relevant to cancer immunotherapy.

Specifically, the engineered cells sense vascular endothelial growth factor (VEGF), a protein found in tumors that directly manipulates and in some ways suppresses the immune response. When the rewired cells sense VEGF in their environment, these cells, instead of being suppressed, respond by secreting interleukin 2 (IL-2), a protein that stimulates nearby immune cells to become activated specifically at that site. Normal unmodified T cells do not produce IL-2 when exposed to VEGF, so the engineered behavior is both useful and novel.

Modular ‘parts’

This work took place in cells in culture, and the technology next will be tested in animal studies.

While Leonard’s team has initially focused on the application of this cell programming technology to enabling cancer immunotherapy, it can be readily extended to distinct cellular engineering goals and therapeutic applications. Leonard’s “parts” are also intentionally modular, such that they can be combined with other synthetic biology innovations to write more sophisticated cellular programs.

“To truly accelerate the rate at which we can translate scientific insights into treatments, we need technologies that let us rapidly try out new ideas, in this case by building living cells that manifest a desired biological function,” says Leonard, who also is a founding member of the Center for Synthetic Biology and a member of the Chemistry of Life Processes Institute.

“Our technology also provides a powerful new tool for fundamental research, enabling biologists to test otherwise untestable theories about how cells coordinate their functions in complex, multicellular organisms,” he says.

The Defense Advanced Research Projects Agency and a Cancer Center Support Grant supported the research.

Source: Northwestern University

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