The human body teems with bacteria. These micro-organisms live on the skin, in mucus membranes, on the eyes and in the gut, among other places. The large intestine alone hosts up to 1,000 different species. According to a study published in the January 28, 2016, Cell, an average human hosts about as many bacterial cells as the cells that make up skin, bone, organs and the rest of the body.
“The way that a host animal’s body interacts with bacteria is fundamental to basic survival,” says Susan Erdman, a researcher who studies comparative medicine at the Massachusetts Institute of Technology in Cambridge. So it’s not surprising that researchers have long studied the interaction between bacteria and cancer.
Depending on the species and location, bacteria may be harmful or protective. Or both: It’s been known for decades that infection with a type of bacteria called Helicobacter pylori may result in ulcers and can lead to stomach cancer in some patients. And yet a large study published in 2008 concluded that patients infected with some strains of H. pylori are at reduced risk of developing esophageal cancer.
H. pylori isn’t the only type of bacteria associated with cancer. Recent investigations suggest that bacteria in the gut also play a role in a patient’s response to many conditions, not only gastrointestinal diseases but other cancers, including melanoma. In addition, there is growing support for the idea that bacteria can be used and modified to help patients—to develop new anti-cancer drugs, to boost the efficacy of existing drugs or to stimulate the immune system to better attack cancer cells.
“We know bacteria can cause cancer. But more than a decade ago, we became interested in how bacteria might instead prevent or treat cancer,” says Erdman. “We want to harness the beneficial effects of bacteria in anti-cancer therapies while minimizing the damaging side effects that infectious agents can have.”
Erdman has spent years studying bacteria and cancer and is optimistic that a deep understanding of how bacteria interact with the immune system will drive new treatments and prevention strategies.
Treating Cancer With Bacteria
More than 200 years ago, physicians observed a connection between bacterial infections and tumor shrinkage—though they didn’t understand the link between the two. In 1813, French physician Arsène-Hippolyte Vautier reported that tumors got smaller in patients who developed severe infections from Clostridial bacteria. About 50 years later, a woman with an inoperable sarcoma visited German physician Wilhelm Busch, who exposed her to erysipelas, a skin infection characterized by high fever and raised red rashes. (Scientists now know that erysipelas is a bacterial infection, but Busch was not aware of that.) Busch tried the treatment because, in previous years, he had observed tumors shrinking in a patient with erysipelas. His sarcoma patient’s tumor regressed, but she died nine days after infection.
In 1891, a young American surgeon named William Coley identified a head and neck cancer patient whose tumor disappeared after a severe erysipelas infection. He suspected, as researchers now believe, that the Streptococcus pyogenes bacteria that cause erysipelas triggered an immune response in the patient’s body that attacked both the infection and nearby cancer cells. Encouraged, he began treating more patients who had no other treatment options with Streptococcus pyogenes, with some success. “Coley’s toxins” remained a cancer treatment option into the middle of the 20th century, when the U.S. Food and Drug Administration (FDA) declared the controversial therapy could not be continued without extensive clinical trials to evaluate its safety and effectiveness. Studies in the 1970s ultimately failed to demonstrate a survival benefit from the treatment.
In the 1960s and 1970s, reports of guinea pig experiments described startling results when the animals’ tumors shrank or vanished after exposure to a bacterium called Bacillus Calmette-Guerin, or BCG. The bacteria, like Coley’s toxins, were believed to trigger an anti-cancer response in the immune system.
Inspired by the guinea pig studies, in the mid-1970s, Canadian urologist Alvaro Morales applied to the National Cancer Institute of Canada for funds to pursue BCG research in bladder cancer patients. His application was denied. He remembers one review slamming the proposal, noting that BCG, which is related to the bacterial strain that causes tuberculosis, was ineffective and dangerous.
Disappointed but undaunted by the rejection, Morales secured funding elsewhere. In the years that followed, he found BCG reduced the risk of recurrent bladder cancer in patients who had undergone bladder surgery. In 1989, the FDA approved BCG for noninvasive bladder cancer, and it remains a standard post-surgery treatment for those patients, even though about 30 percent of them don’t respond to the therapy and its side effects can be serious.
“I’ll never forget that assessment, but the reviewer proved to be wrong over time,” says Morales, who retired from Queen’s University in Kingston, Ontario, in 2004. Now, he says, “there seems to be a renaissance of interest in using bacteria” to treat cancer, as recent studies suggest some bacterial strains may improve treatment efficacy or help with side effects.
About 40 trillion bacteria call the human body home, and the vast majority live in the large intestine. Some are good, some are bad, and some are both. Maintaining a population of helpful bacteria—the kind that ward off disease—is critical to good health, says Sarah Rafat, a senior clinical dietitian at the University of Texas M. D. Anderson Cancer Center in Houston.
Rafat has seen an increase in patients asking about probiotic supplements—pills that contain live, “helpful” bacteria like Lactobacillus and Bifidobacteria that help break down food in the gut.
“Probiotics in general are good, yes, but in the cancer patient population, it depends on the patient,” says Rafat. Treatments like antibiotics, which wipe out good and bad bacteria indiscriminately, can decimate the microbial population of a person’s intestines.
“Having a compromised immune system or being neutropenic can put one at risk of getting an infection,” says Lisa Lillie, a registered dietitian at Vanderbilt-Ingram Cancer Center in Nashville. A person with neutropenia has an abnormally low level of white blood cells called neutrophils that fight infection.
A cancer patient may want to use probiotic supplements in an attempt to re-establish good bacteria, although clinical studies haven’t demonstrated a benefit in using these products. A 2013 study published in
Science suggested a large population of good strains of bacteria increases the effectiveness of chemotherapy—but the study was done on mice, not humans, and didn’t look specifically at supplements. Other studies have associated serious side effects (including pneumonia and endocarditis) with probiotic supplement use in immunosuppressed patients—though the researchers weren’t looking specifically at cancer patients.
Until better evidence becomes available, Rafat and her colleagues recommend that patients wait until treatment is completed before considering probiotic supplements and then discuss them with their health care providers.
“We don’t say don’t ever take it. We tell the patients to hold on until you’re done with treatment,” she says.
In addition, she says, not all supplements contain what their labels advertise; some include ingredients not listed on the label. Supplements do not require approval by the U.S. Food and Drug Administration, and the agency warns consumers to be aware of the risks. Rafat recommends that patients consult with a nutrition expert to ensure the product they are looking at is safe and of good quality.
Lillie agrees. “There are many different probiotics, so discuss which strains and species would be appropriate to take based on the patient’s condition, a trusted manufacturer and suggested dose,” she says.
Both experts note that probiotics occur naturally in foods like yogurt and sauerkraut and in high-fiber foods like leafy green vegetables. The best strategy for incorporating probiotics into a diet is to increase consumption of these foods, says Rafat, rather than taking a pill.
Balancing the Good and the Bad
Bacteria and the immune system are in constant communication, says Erdman. These interactions help determine whether a person has good health or develops disease, and it can be useful, if simplistic, to think of bacteria as being good or bad. Maintaining a strong population of good bacteria, says Erdman, is a sound strategy for keeping disease at bay.
“Good bacteria offer clues to how a body can stay healthy and perhaps stop cancers from growing in the first place,” she says, cautioning that it’s not clear whether altering one’s microbes would be sufficient to prevent cancer. Good bacteria include Lactobacillus, which occurs naturally in yogurt and fermented food and is used to treat digestion problems like diarrhea and irritable bowel syndrome. Lactobacillus is also found in probiotic supplements. (See “Are Probiotic Supplements Right for You?” above.)
Bad bacteria can cause infections. Erdman has led studies on mice showing that certain bacterial infections trigger an immune response that promotes the growth of colon cancer and breast cancer. Of course, people respond differently than mice, but the studies suggest intestinal microbes can influence the growth of cancer elsewhere in the body. Infections can be particularly devastating for cancer patients whose immune systems have already taken a beating from treatment. These patients often receive antibiotics, which kill good and bad germs alike and keep infections at bay. But by killing good bacteria, the antibiotics are inhibiting the immune system.
“What ends up happening is that we inadvertently undermine some of our best defenses to deal with the environment,” says Erdman. “If we’re too clean, we end up removing some of our best friends.”
The right bacterial mix in the gut can make a big difference to cancer patients, whose immune systems are often weakened by treatment and fighting disease. In 2014, a 39-year-old man with T-cell acute lymphocytic leukemia being treated at the Ohio State University James Cancer Hospital, in Columbus, developed a Clostridium difficile infection, sometimes called C. diff, a stubborn condition resistant to many forms of antibiotics that causes severe and potentially life-threatening diarrhea.
“He’d gone through everything we use for C. diff, and he had absolutely no response to any of them,” says leukemia clinical nurse specialist Lisa Blackburn, who worked with the patient (who preferred not to be interviewed for this article). “He’d been in the hospital a couple times at this point and had almost died a couple times from sepsis,”
a serious inflammatory response to an infection that can be fatal.
Blackburn says someone on the patient’s health care team suggested he undergo a fecal microbiota transplant—a procedure in which stool from a healthy donor is transferred directly into a patient’s gut, often via colonoscopy. The earliest documented uses of this approach date back to fourth-century China, but it has become more widespread in the U.S. only in the past few years. The idea is to restore healthy bacteria to the ill person, but Blackburn admits it carries a significant “ick” factor.
“It’s kind of gross for patients to think about, but it’s so effective,” says Blackburn, who described the case study in February 2015 in the Clinical Journal of Oncology Nursing. “This infection that kills so many of our patients really outweighs the grossness of it. I think we’re going to see it more and more.”
She says the patient initially resisted but finally consented. It worked quickly: By the time he returned to his room after the procedure, the patient said he no longer suffered from cramping pain and had an appetite. Blackburn says that the treatment not only helped him that time, but it seemed to reset his gut so the next time he developed C. diff, he responded immediately to conventional treatment.
Blackburn says she has assisted in treating five patients using the procedure, all successfully, and she’s amazed at the results. “I would encourage any patient” with a C. diff infection to discuss it with their physicians, she says.
Patients’ rapid response to the therapy has encouraged her to start a database of patient experiences and prepare user-friendly information about the procedure in an effort to reduce the “ick.”
Harnessing the Power of Bacteria
In recent years, drugs called immune checkpoint inhibitors have extended survival in patients with metastatic melanoma. Study results suggest they may also extend survival in patients with lung, colorectal and kidney cancers. These drugs—including Yervoy (ipilimumab), Opdivo (nivolumab) and Keytruda (pembrolizumab)—effectively release the immune system’s natural brakes on T cells, white blood cells that attack harmful pathogens invading the body. T cells can then attack cancer cells.
But the drugs have a downside: On average, less than a third of patients have a sustained response to them. Most patients develop resistance. Yervoy causes side effects that can be life-threatening. In the face of these obstacles, researchers want to identify patients who are most likely to benefit and increase their number.
Investigations of the gut microbiome indicate bacteria may be key players in whether or not a patient responds to immunotherapy. In a study published in November 2015 in Science, Marie Vétizou at the Institut de Cancérologie Gustave Roussy Cancer Campus in Villejuif, France, and her colleagues injected Yervoy into “germ-free” mice that had tumors. The mice did not respond to the drug, suggesting the lack of bacteria crippled the animals’ immune response. Further studies found that treating mice with antibiotics similarly inhibits Yervoy. When they went looking for effects in a human population, the researchers analyzed the gut microbes of 25 people with metastatic melanoma before and after treatment with Yervoy. They found that Yervoy changed the microbial mix in patients’ intestines. And when they transplanted gut microbes from treated human patients into germ-free mice, the mice receiving samples rich in bacteria called Bacteroides fragilis responded better to treatment with Yervoy than mice in other groups.
In another study from the same issue of
Science, researchers led by Thomas Gajewski at the University of Chicago similarly connected bacteria to the efficacy of immunotherapy. They studied the growth of melanoma in mice with established tumors. In animals given particular bacterial strains as treatment, tumors grew more slowly than in untreated mice. The bacterial treatment slowed tumor growth as much as treatment with an immune checkpoint inhibitor. Treatment that combined the useful bacteria and the immunotherapy drug was even more successful, nearly eliminating tumor growth.
Bacteria may also be “trained” to attack tumor cells. In a study published in April 2015 in
mBio, molecular immunologist Sebastian Felgner, who studies bacteria and cancer at the Helmholtz Centre for Infection Research in Braunschweig, Germany, and his colleagues described a way to genetically alter a strain of Salmonella that could colonize a tumor and activate an immune response against cancer cells. Experiments on mice showed the bacteria colonized sarcomas and kidney and colon tumors, slowing their growth, but failed to remove the tumors completely. Felgner says these bacteria likely won’t be potent enough to work as a stand-alone treatment, but they could boost the outcomes of other treatments or shuttle treatments directly to the tumor.
Part of the problem with developing new therapies, says Erdman, is that researchers still don’t understand exactly what the bacteria are doing. “If we could understand this a little bit better, we might have something at our fingertips that could be readily converted into something” that could treat cancer or boost current treatments.
Morales, the Canadian urologist, agrees. Forty years after his first paper on BCG, the bacteria’s mechanism still isn’t fully understood. “Very smart people have been trying to elucidate the mechanism, and it’s still not clear. We just know little pieces,” he says. “It’s a success story, but we don’t know how it works.”
June 24, 2016