A notorious germ best known for making people rush to the toilet may one day send cancer patients to clinics for a new treatment.
With some genetic modifications, Salmonella typhimurium transformed from a germ that wreaks havoc in the guts of humans to one that can infiltrate deep into the guts of tumors and unleash an immune warfare. This is according to a study published Wednesday in Science Translational medicineSouth Korean researchers reported that the weaponized gut bacteria could prevent cancer from growing in humans and spreading in mice — all without evidence of harmful side effects.
The study is only in mice and much more work is needed to test efficacy and safety in humans. But the researchers are encouraged by the data so far. Overall, it appears that the trained germs “have excellent anticancer effects in diverse mouse tumor models, suggesting that this strategy could be applied to a broad spectrum of malignancies,” the authors conclude.
It’s not the first time researchers have tried to train bacteria as cancer therapies. In fact, there is already one treatment – for bladder cancer – that uses Mycobacterium bovis bacillus Calmette-Guérin (BCG). But many of the other treatments so far have not been very effective and required multiple injections. Even still, tumors usually grow back in the face of those treatments.
For better cancer weapons, a team of researchers led by Chonnam National University biologist Jung-Joon Min turned to S. typhimurium. Like many of its intestinal inhabitants, S. typhimurium will happily squeeze into cramped, necrotic, low-oxygen spaces – the exact conditions within tumors.
First, the researchers disarmed the germ, knocking out a powerful signal that coordinates its disease-causing activities. Without this, the germ is 100,000 to 1,000,000 times less virulent, previous research showed. Next, the researchers re-armed the restrained Salmonella with the gene for making flagellin B. Vibrio vulnificus. Flagellin B, or FlaB, is part of bacteria’s whip-like tail that allows them to swim. It is known to trigger a rapid and strong innate immune response in humans and mice. That immune response should act as a first-line defense against invading bacteria. But it also produces a storm of chemicals and a wave of attacking immune cells that can blow away cancer cells.
The researchers developed their S. typhimurium soldiers to release FlaB only when it got a harmless sugar signal. That way it didn’t randomly trigger intense immune responses.
To test their cancer-seeking bacteria, Min and the team started by implanting and injecting mouse tumors into mice and then injecting the bacteria into their tails. Initially, the bacteria accumulated in the spleen and liver of the rodents. But three days later, the germs would spread almost exclusively on the inside of tumors.
After getting the sweet FlaB trigger to work, the team found that the bacteria were able to significantly shrink or eliminate the tumors. In one experiment, the triggered bacteria completely blew away tumors in 11 of 20 mice.
The researchers then repeated the experiment with mice that had human colon cancer tumors implanted in their intestinal wall. After 27 days, a control group of seven animals – which were implanted with cancer but did not receive a bacterial injection – had a total of 91 tumors. Eight treated mice had only four relatively small tumors (three mice had tumors and five were tumor-free).
By dissecting the tumors, the researchers confirmed that the bacteria penetrated deep into the tumors, releasing FlaB and triggering an intense innate immune response. Still, the animals showed no signs of severe inflammation or other side effects, suggesting the treatment was safe.
While there are many more animal and human studies to come, so far the authors conclude that their cancer-seeking germs trigger “a potent immune response against cancer.”
Science Translational medicine2017. DOI: 10.1126/scitranslmed.aak9537 (About DOIs).