Cancer, Scientific

Hacking into macrophage attack circuits, Stanford scientists pitch a better early-warning alert system for tumors

After years of fine tuning ways to enlist the immune system in the fight against cancer, immunotherapy has taken the field by storm, with a Nobel prize and a pair of blockbuster checkpoint drugs to boast. But can immune cells help in an even broader effort — flagging malignant tumors before they are detectable by traditional instruments?

Pushing the threshold of cancer diagnoses to earlier and earlier stages of the disease is one of the Holy Grails in oncology, inspiring multimillion-dollar investments into startups like Grail. This week, a team from Stanford has chipped in with their own pitch and some mouse data to show for it.

Pioneering a new definition of the concept “immunodiagnotics,” Sanjiv “Sam” Gambhir of Stanford’s Canary Center for Early Detection repurposed macrophages to report the presence of disease or damaged cells, achieving detection of tumors as small as 4 millimeters in diameter, outperforming “some of the most advanced early tumor detection methods out there.”


Image: Sanjiv “Sam” Gambhir. Steve Fisch, STANFORD

His technique, reported in Nature Biotechnology, makes use of macrophages’ innate ability to find (and eat) malfunctioning or dead cells. That’s simple; the big challenge is to hack the process in a way such that these immune cells emit a detectable signal before they begin to feast.

To do that, Gambhir’s team tagged a molecular marker to a gene promoter that awakens and activates the gene directing the macrophage onslaught in the presence of a tumor.

“The molecular marker is called Gaussia luciferase, and under certain chemical circumstances, it glows,” Gambhir said in a statement. “So the idea is, we pick a gene that turns on when a macrophage senses a tumor cell, we link that gene’s promoter to Gaussia luceriferase and finally, we integrate it into the macrophages.”

Macrophages have been a key immune cell type of interest, attracting a number of biotechs to remove the “don’t eat me” signal that tumors often deploy to prevent an attack.

There are, of course, limitations with the method. For one, macrophages don’t just respond to cancerous targets, so a “hit” on this test represents a call for other, confirmatory tests rather than a definitive diagnosis. But the approach, which involves creating a synthetic biomarker, is a major departure from the traditional practice, which relies on identifying biomarkers in the body.

The synthetic nature of this technique means the strategy can be applied to multiple instruments and immune cells — all possibilities that Gambhir is exploring with his startup, Earli.

Moving forward, Gambhir plans to test the method in other types of cancers and animal models, while refining the technique to home in on just tumor cells, not cells with other types of damage.


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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
Director of Operations
Atlas Venture Cambridge, MA

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