Researchers at Columbia University created a genetically modified bacterium that expresses a molecular cloak to help the bacterial cells stay hidden from the immune system. They have shown the potential of this bacterium as an anti-cancer therapeutic by engineering the same bacteria to also express an anti-tumor toxin, allowing them to accumulate in and destroy tumors in mice. The new approach could help unlock the potential of bacterial therapies for a variety of cancers.
The idea of using bacteria to target a tumor sounds a little strange at first. After all, our immune system has evolved potent defenses against bacteria it encounters in the blood, and large numbers of bacterial cells in the blood can result in very high levels of inflammation and toxicity. However, if the bacteria can be shielded from the immune system, temporarily, then they can begin to exert a therapeutic effect at a tumor site before eventual detection and destruction by the immune system.
This concept is at the heart of a new technique which aims to enhance a naturally-occurring bacterial cloaking mechanism that shields bacterial cells from immune detection. This involves capsular polysaccharides (CAP), which are sugar molecules that certain bacteria express on their surface. “We hijacked the CAP system of a probiotic E. coli strain Nissle 1917, ”said Tetsuhiro Harimoto, a researcher involved in the study. “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. ”
To create that on / off switch, the researchers developed an inducible CAP (ICAP) system, whereby they could affect the amount of CAP expressed by bacteria using an external signal in the form of a molecule called IPTG. Co-administering IPTG and the ICAP bacteria allows for a given duration of immune protection, and changing the amount of co-administered IPTG lets the researchers to control this. Engineering the bacteria to also express an anti-tumor toxin turns them into a bioweapon against cancer that can reach and stay at the tumor site for long-term efficacy. So far, the researchers have shown that the system can help to shrink tumors in mouse models.
“What’s really exciting about this work is that we are able to dynamically control the system,” said Tal Danino, another researcher involved in the study. “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. ”
Study in Nature Biotechnology: A programmable encapsulation system improves delivery of therapeutic bacteria in mice
Via: Columbia University