Genetically Engineered, Sound-Controlled Bacteria That Seek and Destroy Cancer Cells

Since its inception, chemotherapy has proven to be a valuable tool in treating many kinds of cancers, but it has a significant drawback. In addition to killing cancer cells, it can also destroy healthy cells like the ones in hair follicles, causing baldness, and those that line the stomach, producing nausea.

Now, scientists at the California Institute of Technology (Caltech) may have a better solution: genetically engineered, sound-controlled bacteria that seek and destroy cancer cells. In a new paper that was published in the journal

“The goal of this technology is to take advantage of the ability of engineered probiotics to infiltrate tumors, while using ultrasound to activate them to release potent drugs inside the tumor,” professor Shapiro says.

A strain of E. coli called Nissle 1917, which is approved for medical uses in humans, was the starting point for their work. After being injected into the bloodstream, these bacteria spread throughout the body. The patient’s immune system then destroys them—except for those bacteria that have colonized cancerous tumors, which offer an immunosuppressed environment.

To transform the bacteria into a useful tool for treating cancer, the research team engineered them to contain two new sets of genes. One set of genes is for producing nanobodies, which are therapeutic proteins that turn off the signals a tumor uses to prevent an anti-tumor response by the immune system. The presence of these nanobodies allows the immune system to attack the tumor. The other set of genes act like a thermal switch for turning the nanobody genes on when the bacteria reaches a specific temperature.

By inserting the temperature-dependent and nanobody genes, the team was able to create strains of bacteria that only produced the tumor-suppressing nanobodies when warmed to a trigger temperature of 42-43 degrees

Through a series of trials, the researchers found that mice treated with this strain of bacteria and ultrasound showed much slower tumor growth than mice treated only with ultrasound, mice treated only with the bacteria, and mice that were not treated at all.

However, the team also found that some of the tumors in treated mice did not shrink at all.

“This is a very promising result because it shows that we can target the right therapy to the right place at the right time,” Shapiro says. “But as with any new technology there are a few things to optimize, including adding the ability to visualize the bacterial agents with ultrasound before we activate them and targeting the heating stimuli to them more precisely.”

Reference: “Ultrasound-controllable engineered bacteria for cancer immunotherapy” by Mohamad H. Abedi, Michael S. Yao, David R. Mittelstein, Avinoam Bar-Zion, Margaret B. Swift, Audrey Lee-Gosselin, Pierina Barturen-Larrea, Marjorie T. Buss and Mikhail G. Shapiro, 24 March 2022, Nature Communications.
DOI: 10.1038/s41467-022-29065-2

Funding for the research was provided by the Sontag Foundation, the Army Institute for Collaborative Biotechnologies, and the Defense Advanced Research Projects Agency.

The researchers’ paper, “Ultrasound-controllable engineered bacteria for cancer immunotherapy,” appears in the March 24 issue of Nature Communications. Shapiro’s and Abedi’s co-authors include Michael S. Yao (BS ’21), formerly of Caltech and now at the University of Pennsylvania, who is co-lead author; David R. Mittelstein (MS ’16, PhD ’20), formerly of Caltech and now at UC San Diego; Avinoam Bar Zion, visitor in chemical engineering at Caltech; Margaret B. Swift of the Howard Hughes Medical Institute; Audrey Lee-Gosselin, formerly of Caltech and now at the Indiana University School of Medicine; Pierina Barturen-Larrea, research technician in Caltech’s Division of Chemistry and Chemical Engineering; and Marjorie T. Buss, graduate student in chemical engineering.