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Will Programmable Immune “Cellbots” Be the Next Weapon Against Cancer?

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clinical trial of its synNotch cells in 2018. The firm announced $34 million in financing in June, adding up fees from the Kite deal and venture capital investments from Kite, Kleiner Perkins Caulfield & Byers, and others. Cell Design Labs will help build new functions into the T cell therapies of Kite, which is now considered the front-runner in the race for the first CAR-T approval. (With its equity stake Kite has placed CEO Arie Belldegrun on the Cell Design Labs board.)

[This paragraph previously attributed an incorrect description of synNotch to Chen. We apologize for the error.] There are many questions to answer as the company pushes toward clinical trials. The first is how to efficiently engineer human cells that can produce multiple “outputs,” which is “far from a solved problem,” says UCLA’s Chen. Will all the synthetic parts, even if they work correctly in a human cell, trigger an immune reaction? That’s another question, says Chen.

Even if the cells work like cells should, and the body accepts them, will they stay around long enough to kill cancer? Cancer also is excellent at evading attack; one of the synNotch cells’ strengths—recognizing two targets instead of one—is also a potential weakness. If you need two targets, there’s double the chance that the cancer can mutate away” from the cells’ attack, says Wilson Wong, a former post-doc in Wendell Lim’s lab. He now runs his own lab at Boston University, also pursuing synthetic biology and immuno-oncology. (Wong praises the synNotch work—“I’m jealous; nothing out there compares to it”—with the disclosure that his work many years ago made a small contribution to Lim’s synNotch program.)

The idea of turning a patient’s own cells into tiny drug factories might sound familiar to biotech observers. The Cambridge, MA, startup Moderna Therapeutics has raised more than $1 billion from investors and partners to inject pieces of chemical code into a patient’s cells and let the cells pump out the drug that the patient needs. Moderna has begun testing some of its products in humans, but it has not yet produced any data.

Lim is aware of Moderna’s work, and he says there are big differences. Mainly, his T cells are programmed outside the body, then sent back in to crawl through the body and attack only the tumors they’ve been sent to find, like a police dog remembering the scent of a fugitive from a piece of clothing.

Lim’s synNotch cells might not be the first experimental live drugs, made with synthetic biology, to be tested in humans. Synlogic of Cambridge, MA, is engineering microbes to seek out and correct disease states, such as the toxic buildup of the amino acid that causes the rare disease phenylketonuria. The company could run its first trial in 2017, although CEO Jose-Carlos Gutierrez Ramos told Xconomy earlier this year that such treatments would “clearly have a different type of regulatory scrutiny—and they should.”

Until now synthetic biology has mainly been associated with production of new fragrances and eco-friendly fuels pumped out by yeast or microbes that have been rewired to do things nature never intended. (For more background, a conversation with one of the field’s pioneers is here and here.)

Rewiring human cells is going to be a bigger challenge. “It’s fundamentally different from and significantly more complex than microbial engineering,” says Chen.

Lim doesn’t downplay the challenge, but he stresses that synNotch is not an overhaul. “We’re not trying to completely rebuild a T cell,” he says. “We’re trying to take advantage of what’s there and change how its decisions are made.”

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