UC researchers develop new probiotic to battle and break the defenses of most cancers cells

Bacteria usually have a bad reputation, if you first think of certain strains that can cause serious illnesses such as pneumonia or meningitis. However, there are many helpful bacteria known as probiotics that help the body in different ways.

University of Cincinnati researchers have now developed a probiotic that aims to fight and break down cancer cells’ defenses to give therapies an easier way to kill tumors. The results were recently published in the journal Advanced Healthcare Materials.

Nalinikanth Kotagiri, PhD, lead author on this study, assistant professor at UC’s James L. Winkle College of Pharmacy, and a member of the UC Cancer Center, investigates “solid cancers” or those defined as abnormal cell growth in “solid” organs, such as: Breast or prostate, as opposed to leukemia, a cancer that affects the blood. Kotagiri explains that many solid cancers have an extracellular matrix made up of collagen and hyaluronic acid. The matrix forms a barrier around the cells, making it difficult for antibodies and immune cells to reach the tumors.

Shindu Thomas, the first author of this study and PhD student at the Kotagiri laboratory, worked with E. coli Nissle, a bacterium that has been used as a probiotic for around 100 years and is different from E. coli strains that cause disease. With a new technology, any protein or enzyme can be produced on the E. coli Nissle bacteria.

In this case, the bacteria were engineered to secrete an abundance of smaller structures on the outer edge of the cells called the outer membrane vesicles. The vesicles contain the same materials as the bacteria themselves, so the researchers engineered the bacteria to carry an enzyme that breaks down the extracellular matrix of cancer.

Kotagiri said bacteria tend to thrive in oxygen-poor and immunodeficient environments, two traits found in solid cancers. Because of this, the specially developed bacteria are naturally attracted to these cancers.

We used this unique feature of E. coli Nissle to locate and localize these tumors. And when bacteria have settled there, they form nanoscale vesicles that carry the enzyme much deeper into the tumor matrix. “

Nalinikanth Kotagiri, PhD, lead author on the study

After developing the new probiotic, the researchers studied the effects of the bacteria on animal models of breast and colon cancer. The bacteria are given intravenously about four or five days before cancer treatment, so the bacteria have time to colonize and break down the cancer’s defenses and prepare it for treatment.

After administration of the bacteria and subsequent doses of immunotherapy or another drug used in targeted therapy, the mice survived twice as long compared to those given cancer therapy alone, according to Kotagiri. The imaging showed that the bacteria and enzyme were effective in breaking down the extracellular matrix and allowing the therapy to reach the cancer cells.

The study found that the bacteria affected the tumors but did not attack healthy cells in other organs such as the heart, lungs, liver, and brain. Kotagiri said this shows that the bacteria can be safe and not cause infections in other parts of the body, but more research needs to be done to examine their safety in large animal models and potentially in humans, particularly in immunodeficient environments.

“This always comes with a word of caution as to how you can use this strategy without causing sepsis or open infections in the body,” he said.

Kotagiri said that around 2018 his lab began studying more closely how bacterial probiotics can address biomedical problems, since there are roughly one to twice as many bacterial cells as human cells in your body at any given time.

“There are bacteria in the intestines, on the skin, in the lungs, in the mouth, even in tumors,” said Kotagiri. “So why not take advantage of this and find interesting ways to make them a little more proactive?”

If the manipulated bacteria continue to prove safe and effective, Kotagiri says there are a multitude of ways the bacteria can evolve for various purposes, including possible uses of the bacteria to treat conditions in the intestines, mouth, and skin. There is also the potential for the multi-protein and molecule-armed bacteria to evolve into a monotherapy platform (or therapy with one type of treatment) rather than just allowing combination therapy, he said.

“So the bacteria can essentially serve as a mother ship that carries the necessary therapeutic payload to unique niches in the body and from there is a self-sustaining unit,” said Kotagiri. “While the possibilities are endless, there are also significant challenges. We have to be good administrators to enable this type of evidence for the community to understand the limits and what can be done.”

Source:

Journal reference:

Thomas, SC, et al. (2021) Genetically modified bacteria improve immunotherapy and targeted therapy through stromal remodeling of tumors. Advanced healthcare materials. doi.org/10.1002/adhm.202101487.