Ultrasound-controlled bacteria could become cancer immunotherapy

A new immunotherapy treatment uses sound-controlled, genetically modified bacteria that seek out and destroy cancer cells

For several decades, Chemotherapy has proven to be a valuable tool in the treatment of many types of cancer, but it has a major drawback. In addition to killing cancer cells, it also can destroy healthy cells such as those found in hair follicles, causing baldness, and those lining the stomach, causing nausea.

Now, scientists at the California Institute of Technology (Caltech) may have a better solution as new immunotherapy treatment: sound-controlled, genetically modified bacteria that seek out and destroy cancer cells. In a new article public in the magazine Nature Communications the scientists of the laboratory directed by Mikhail Shapiro, professor of chemical engineering and researcher from the Howard Hughes Medical Instituteshow how they have developed a specialized strain of the bacterium Escherichia coli ( E. coli) that seeks out and infiltrates cancerous tumors when injected into a patient’s body. Once the bacteria have reached their destination, ultrasound pulses can activate them to produce anticancer drugs.

“The goal of this technology is to harness the ability of engineered probiotics to infiltrate tumors, while using ultrasound to activate them and release powerful drugs within the tumor”, explained Professor Shapiro. a strain of E. coli called Nissle 1917, which is approved for medical use 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 provide 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.

To transform the bacteria into a useful tool for treating cancer, the research team designed them to contain two new sets of genes. One set of genes is used to produce nanobodies, which are therapeutic proteins that turn off signals used by a tumor to prevent an antitumor response from the immune system. The presence of these nanobodies allows the immune system to attack the tumor. The other set of genes acts as a thermal switch to turn on the nanobody’s genes when the bacterium reaches a specific temperature.

By inserting the nanobody and temperature-dependent genes, the team was able to creating strains of bacteria that only produced tumor-suppressing nanobodies when heated to an activation temperature of 42-43 degrees Celsius (107.6-109.4 degrees Fahrenheit). Since the normal temperature of the human body is 37 degrees Celsius (98.6 degrees Fahrenheit), these strains do not start producing their antitumor nanobodies when injected into a person. Instead, they grow silently inside tumors until an external source heats them to their activation temperature.

But, How do bacteria that are in a specific place, potentially deep in the body where a tumor is growing, get heated? To do this, the team used focused ultrasound (FUS), which is similar to the ultrasound used to image internal organs or a fetus growing in the womb, but has a higher intensity and focuses on a narrow spot. . Focus ultrasound at a point causes the tissue at that location to heat up, but not the surrounding tissue; by controlling the intensity of the ultrasound, the researchers were able to raise the temperature of that tissue to a specific degree.

After giving the bacteria time to infiltrate the tumors, the team used ultrasound to heat them.

“Focused ultrasound allowed us to activate the therapy specifically within a tumor. This is important because these powerful drugs, which are so useful in treating tumors, can cause significant side effects in other organs where our bacterial agents may also be present.”, accurate Mohamad Abedi (PhD ’21), a former doctoral student in Shapiro’s group who co-led the project and is now a postdoctoral fellow at the University of Washington.

To test whether their engineered strain of bacteria worked as intended, the research team injected tumor-stricken lab mice with bacterial cells. After giving the bacteria time to infiltrate the tumors, the team used ultrasound to heat them up. 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 with ultrasound alone, mice treated with the bacteria alone, and mice that did not receive no treatment.

Nevertheless, the team also found that some of the tumors in the 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. But as with any new technology, there are a few things to optimize, including adding the ability to visualize bacterial agents with ultrasound before we activate them and direct the heat stimuli more precisely,” Shapiro concluded.