Immunotherapy’s effectiveness may depend on the bacteria living in patients’ gastrointestinal tracts, studies show.
BY LAURIE TOICH
PUBLISHED June 21, 2018
COULD THE SUCCESS OF immunotherapy rest on what kinds of bugs reside in your gut? Recent research findings suggest yes — and point to steps that could help patients get the right microbiotic mix before beginning this type of treatment.
Specific strains of intestinal bacteria increase the response rate to immunotherapy in patients with advanced melanoma and some other cancer types, according to results from three studies published recently in the journal Science.
Although immunotherapy has improved cancer treatment, just 35 percent of patients with melanoma respond well, indicating a need for better therapies, according to Thomas Gajewski, M.D., Ph.D, the AbbVie Foundation Professor of Cancer Immunotherapy at University of Chicago Medicine and a leader of one of the studies.
His team found that the presence of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium in the intestines was much higher among patients who responded to immunotherapy compared with nonresponders.
The investigators noted that the presence of these bacteria in the gut may boost the infiltration of T cells, the body’s army against dangerous invaders, into the tumor microenvironment. The bacteria were also found to strengthen T cells’ ability to kill cancer cells.
These findings suggest a cause-and-effect relationship between gut bacteria and response to immunotherapies known as checkpoint inhibitors, according to the investigators. These drugs quiet the activity of the proteins PD-1 or CTLA-4, known as immune checkpoints because they prevent the immune system from overreacting to invaders. Without the influence of these proteins, the immune system can ramp up and attack cancer.
“Specific bacteria clearly contribute to improved anti-tumor immunity in patients,” Gajewski said. “The gut microbiota have a more profound effect than we previously imagined.”
Previous findings in mice had linked the presence of certain gut bacteria to a better response to immunotherapy. “We knew there were multiple barriers that can decrease the odds that immunotherapy will work,” Gajewski said. “We initially thought the microbiome was a minor component. But in our current study, these bacteria were a very strong predictor of who would respond.”
That study included 42 patients who received checkpoint inhibitor immunotherapy for melanoma — 38 were treated with PD-1 inhibitors and four with a CTLA-4 inhibitor. Patient stool samples were collected prior to treatment to analyze bacteria.
The authors focused on eight types of bacteria found in higher levels among patients who responded to treatment and two species that were more common among patients who did not respond. They defined the bacteria common in responders and the bacteria found more often in nonresponders as beneficial and nonbeneficial, respectively. Patients who had a higher ratio of beneficial to nonbeneficial bacteria achieved a clinical response, according to the authors.
Next, the authors collected fecal bacteria from three patients who responded to immunotherapy and three who did not. The bacteria were transferred to the intestines of germ-free mice that were then implanted with melanoma cells and treated with PD-1 inhibitors. Tumors were observed to shrink in mice only if they had gut microbiota — a defined spectrum of bacterial species — from patients who had responded to the treatment.
These findings suggest that gut bacteria play an important role in cancer immunotherapy response. “Our results strongly suggest that the microbiota is a major factor — a gatekeeper for the immune response against a tumor,” Gajewski said. “Without microbial support, the immune response just never quite gets going.”
Future clinical trials should test the effectiveness of Bifidobacteria as a method to enhance immunotherapy, the study authors concluded: “Our current results open the avenue … for maximizing the ability to predict which patients are likely to respond to immunotherapies such as anti–PD-1.”
The authors also noted that they hope to discover additional gut bacteria that can improve immune response to cancer — and, according to findings published alongside theirs in Science, their peers at other institutions are doing just that.
BACTERIA AND LONGER SURVIVAL
At the University of Texas MD Anderson Cancer Center in Houston, a team identified another group of bacteria associated with a good response to immunotherapy. Their study, conducted in 89 patients with metastatic melanoma, was partially funded by the National Cancer Institute (NCI), which summarized the results in its blog, Cancer Currents.
The investigators found that patients whose guts contained many of these so-called “good” bacteria — the genus Faecalibacterium, of the Ruminococcaceae family and Clostridiales order — experienced a longer progression-free survival than patients with fewer of the bugs, MD Anderson reported in a press release.
Also, patients with a more diverse mix of gut bacteria responded better to immunotherapy, according to the team led by Jennifer Wargo, M.D., an associate professor of surgical oncology and genomic medicine.
The scientists followed up with lab research showing that patients with more good bacteria had more cancerkilling immune cells in their tumors, whereas patients with higher numbers of “bad” bacteria — those of the Bacteroidales order — had tumors that carried more immune-suppressing cells. Like Gajewski’s team, the scientists put human melanoma tumors and gut bacteria into mice, and they found that only the animals with the good bacteria responded to the medication.
Additional analysis showed that responding patients with high levels of the beneficial Ruminococcaceae/ Clostridiales had greater T-cell penetration into tumors and higher levels of circulating T cells that kill abnormal cells. Patients with abundant Bacteriodales had more circulating regulatory T cells and myeloid-derived suppressor cells, as well as a blunted cytokine response — all of which dampened anti-tumor immunity, according to the press release. A third set of good bacteria in PD-1 immunotherapy responders — Akkermansia muciniphila — was identified in a study led by Laurence Zitvogel, M.D., of the Gustave Roussy Cancer Campus in Villejuif, France.
That study in patients with advanced lung, kidney or bladder cancer also established that antibiotics, taken for infection within a couple of months of immunotherapy’s first dose, resulted in shorter life spans, according to the NCI.
So, what does all that mean for patients with cancer? Especially as this concept and ways to act on it mature, those who are eligible for immunotherapy should do all they can to prepare their microbiomes and help their immune systems kick in.
People’s microbiomes can be changed through diet, exercise, antibiotic or probiotic use or transplantation of fecal material, Vancheswaran Gopalakrishnan, Ph.D., a lead author of the MD Anderson study, said in a press release.
A 24-week phase 1 trial in Israel (NCT03353402) is testing fecal transplantation in patients with metastatic melanoma that did not respond to immunotherapy. Through infusion administered during colonoscopy, participants will receive stool provided by fellow patients who responded to immunotherapy, after which they will swallow stool capsules.
Study leaders want to determine whether the strategy will cause side effects, as well as learn whether it will positively change the composition of patients’ gut microbiota and thus increase the number and activity of cancer-killing immune cells.
Interested patients can ask their doctors if any of these strategies might be helpful and if they are available as part of standard care or through clinical trials.