Researchers from the Columbia Engineering program have devised a "cloaking" technique that temporarily hides therapeutic bacteria from immune systems, allowing them to deliver pharmaceuticals more efficiently to tumors and kill cancer cells in mice. They built gene circuits that govern the bacteria surface by modifying the germs' DNA, resulting in a molecular "cloak" that encases the bacteria.

"What's really exciting about this work is that we are able to dynamically control the system," said Tal Danino, associate professor of biomedical engineering, who co-led the study in partnership with Kam Leong, Samuel H. Sheng Professor of Biomedical Engineering. "We can regulate the time that bacteria survive in human blood, and increase the maximum tolerable dose of bacteria. We also showed our system opens up a new bacteria delivery strategy in which we can inject bacteria to one accessible tumor, and have them controllably migrate to distal tumors such as metastases, cancer cells that spread to other parts of the body."

The researchers focused on capsular polysaccharides (CAP), sugar polymers that coat bacterial surfaces, for their study, which was just published in Nature Biotechnology. Many bacteria in nature use CAP to defend themselves against threats, and would apply to immune system attacks as well.

"We hijacked the CAP system of a probiotic E. coli strain Nissle 1917," said Tetsuhiro Harimoto, a PhD student in Danino's lab who is the study's co-lead author. "With CAP, these bacteria can temporarily evade immune attack; without CAP, they lose their encapsulation protection and can be cleared out in the body. So we decided to try to build an effective on/off switch."

Keeping bacteria on the good side

While employing bacteria for therapy is a novel, alternative strategy to treating a wide range of cancers, it comes with a few drawbacks, the most significant is their toxicity. These bacteria, unlike many traditional medications, are living and can spread throughout the body. When entering the body, the ideal bacteria should be able to bypass the immune system and quickly reach the tumor. To reduce toxicity, they must be removed from other sections of the body once they have entered the tumor. Schematics of the (iCAP) system. Source: Tetsuhiro Harimoto, Jaeseung Hahn, Kam Leong and Tal Danino/Columbia Engineering

The researchers employed mouse tumor models to show that by using iCAP, they were able to boost the maximum acceptable dose of bacteria by tenfold. The E. coli strain was encapsulated to allow it to bypass the immune system and reach the tumor. Because no IPTG was given to the E. coli iCAP in the body, it lost its wrapping over time and was easier to remove in other areas of the body, reducing toxicity.

Clinical translation is the next significant obstacle for the team, which is also linked with Columbia's Herbert Irving Comprehensive Cancer Center and Data Science Institute. "While there is a good deal of laboratory research showing various ways to engineer microbes, it is very difficult to apply these powerful therapies to a complex animal or human body. We've shown proof of concept in mouse models, but given that humans are 250 times more sensitive to bacterial endotoxins than mice, we expect our results may have an even bigger effect on human patients than on mice," said Harimoto.

Leong added, "Bacterial cancer therapy holds unique advantages over conventional drug therapy, such as efficient targeting of the tumor tissue and programmable drug release. Potential toxicity has been limiting its full potential. The cloaking approach presented in this study may address this critical issue."