Scientists Look in the Toilet in Search for New Cancer TreatmentBy
Biotechs seek ways to harness gut bugs for immune therapy
"If you ignore the microbiome, you’re making a big mistake"
Scientists seeking to supercharge advanced cancer drugs are looking in an unexpected place for inspiration: the toilet.
New research suggests a link between the trillions of bugs that inhabit the bowels and the effectiveness of immune therapies--drugs that tap the body’s defenses to fight tumors. That has spurred companies worldwide to start delving into patients’ stools in search of a better understanding of microbes in the digestive system.
Those tiny colonizers, part of the body’s first line of defense against infection and with a mix that’s unique to every patient, can affect people’s susceptibility to disease as well as their response to treatment. At least a half-dozen biotech startups are jostling to turn that science into a commercial product to target the immune system via the gut, and at least two companies aim to begin testing experimental treatments on patients by next year.
“The biotech sector really started paying attention when the current hot drugs of immune therapy started getting implicated” with the gut flora, says Jonathan Peled, a bone marrow transplant physician at Memorial Sloan Kettering Cancer Center in New York.
While immune therapies show vast promise, and their annual sales may triple to $22 billion by 2020, they’ve only been proven to work on a small minority of cancer patients. They also often trigger brutal and unpredictable side effects such as hepatitis and colitis, an inflammation of the gut that can cause debilitating diarrhea. Market leaders Merck & Co., AstraZeneca Plc, Bristol-Myers Squibb Co. and Roche Holding AG would stand to make billions more if their medicines worked in more people with fewer toxic reactions.
Investors ranging from venture capitalists Seventure Partners and Flagship Pioneering Inc. to pharma giants Bristol-Myers and Johnson & Johnson have pledged at least $125 million to cancer microbiome startups in recent years. Clustered around Paris and Boston, the new companies have analyzed tens of thousands of stool samples, which are mostly bacteria from the wall of the gastrointestinal tract. “Today it’s as common as collecting blood,” says Pierre Belichard, CEO of French biotech Enterome SA.
The gut microbiome’s link to immune therapies draws on a pair of pioneering research papers published in 2015. One showed how fecal transplants from human patients treated with an immune oncology drug kick-started the medicine’s effectiveness in mice. The other found that certain bacteria combined with a second immune drug froze tumor growth. “There was a wow factor” in the results, says Isabelle de Cremoux, Seventure’s chief executive officer. Her firm has invested in Enterome and four other companies working on cancer microbiome projects.
The bacterial ecosystem may help doctors reach three key goals to make immune therapies work better. The first is to better determine who can be helped. Second is how to tweak the body’s defenses so more patients respond to treatment. And third, how to prevent a common side effect: the immune system attacking the gut. Further off, but more tantalizing, would be a treatment that leverages gut bacteria to fight, or even prevent, cancer.
All those betting on this nascent field face the same question: how to turn the science into a product that’s safe and effective. It’s still unclear which bugs are most beneficial and whether it’s better to place them in the body via a fecal transplant or an oral pill, or whether researchers should focus on drugs based on their effects. The scientific challenge will be to identify the “best ecosystem,” a combination of bacteria that’s effective and not toxic, says Laurence Zitvogel, a researcher at the Institut Gustave Roussy, a cancer center near Paris. She led one of the groundbreaking mouse trials and started EverImmune, a company to test potential therapies.
Belen Garijo, health-care chief at Germany’s Merck KGaA, cautions that it’s unclear whether the approach will be effective once it moves from lab mice to humans. “We haven’t seen any real data yet,” says Garijo. Seres Therapeutics Inc., which is researching the microbiome to fight a wide range of diseases, last year failed to prove the effectiveness of an experimental treatment for a bacterial infection known as C. difficile that had shown promise in earlier tests.
The difference between the C. difficile project and cancer is that to prevent infection, doctors try to restore patients’ good gut bugs to beat out the bad ones. In oncology, the goal is to “perturb the immune system in a beneficial way,” rousing it into action to attack cancer cells, says David Cook, Seres’s chief scientific officer. “There’s some indirect evidence, but very strong indirect evidence, that the microbiome can do that.”
Companies must now focus on converting “shots on goal” into something that will reliably help patients, says Carl Decicco, head of drug discovery at Bristol-Myers. The U.S. immune oncology pioneer signed a deal last November to work with Seventure’s Enterome, and by next year expects to start two human trials involving gut-bug cancer research. “We have high hopes,” Decicco says. In the pharma industry these days, “if you ignore the microbiome, you’re making a big mistake.”