Bacterial Mix Enhances Immunotherapy Response

A mixture of 11 types of bacteria dramatically improves the effectiveness of checkpoint inhibitors in mice, a study reveals. Because the strains have potential for the treatment of multiple cancers, clinical trials of a bacteria–drug combination could begin soon.

Studies have shown that the intestinal microbiome influences patients' response to immunotherapy. Researchers are now trying to determine how best to harness commensal bacteria to boost the effectiveness of checkpoint inhibitors. For example, clinical trials are testing fecal transplants in patients with melanoma who are receiving the drugs. A subset of gut bacteria might provide the same benefits and could be safer, but researchers aren't sure which species will be most helpful.

To pin down which bacteria ramp up the immune response, Kenya Honda, MD, PhD, of Keio University School of Medicine in Tokyo, Japan, and colleagues administered fecal samples from healthy people to germ-free mice. The researchers gauged the samples' effects on the immune system by measuring IFNγ+ CD8+ T-cell induction in the colon. Honda and colleagues then transferred intestinal contents from the mouse that showed the strongest response to other germ-free mice and treated these animals with antibiotics to home in on the responsible bacteria. Next, they cultured bacteria from the animals with the largest increase in IFNγ+ CD8+ T cells and conducted ribosomal RNA sequencing to identify the strains.

That procedure allowed the researchers to pinpoint 21 types of bacteria. Levels of IFNγ+ CD8+ T cells were about twice as high in mice inoculated with these 21 strains than in mice that received no bacteria. In addition, the researchers found they could produce the same effect by giving the animals just 11 of the bacterial types. A mixture containing the remaining 10 strains was less effective than the 11- or 21-strain mixtures, however. Further analysis of the 11-strain combination indicated it doesn't trigger inflammation and appears to stimulate dendritic cells, which in turn induce IFNγ+ CD8+ T cells.

To measure the bacteria's impact on responses to checkpoint inhibitors, the team administered the 10- and 11-strain combinations to germ-free mice and then implanted the rodents with colon tumor cells and gave them anti–PD-1 therapy. The mixture containing 11 bacterial varieties increased the effectiveness of the checkpoint inhibitor. After 3 weeks, tumors in mice that received 10 strains were more than five times larger than tumors in mice that received 11 strains.

Honda and colleagues also tested the bacterial blend in mice with normal intestinal flora. The rodents were implanted with colon cancer cells or melanoma cells and then received anti–PD-1 or anti-CTLA4 treatment. The 11-strain mix improved the animals' responses to both drugs in both cancers.

“They did a really nice job,” says Scott Bultman, PhD, of the University of North Carolina School of Medicine in Chapel Hill, who wasn't connected to the study. “It's a solid approach.” Testing the bacteria in normal mice was particularly important, he says, because it shows that they boost immunotherapy in animals that aren't germ-free and thus are similar to patients. However, he cautions, the bacterial varieties the researchers pinpointed may not be the only ones that could work. “I think it's great that the authors identified these 11 strains, but I don't think there's anything magical about them.”

Honda and his colleagues are working with Vedanta Biosciences to organize a clinical trial of a bacteria–drug combination. “We believe the isolated 11 strains have great biotherapeutic potential and could be applicable to enhancing the treatment of cancer,” he says. –Mitch Leslie