Why does cancer immunotherapy work for some patients, but not others?
Gut biodiversity could play a decisive role, two new studies in Science suggest. A lush microbiome populated with “good bacteria” can boost the power of the treatments, one paper found. On the other hand, certain immunotherapies were less effective in patients who were taking antibiotics that depleted the gut of important flora, according to the second study.
The new studies, published Thursday, add to a growing body of research suggesting that the composition of gut bacteria can fairly dramatically affect how well cancer treatments work.
“I think they’re fascinating studies, and well-done,” said Matthew Krummel, a professor of pathology at the University of California, San Francisco, who first developed the cancer immunotherapy drug Yervoy and was not involved in the new research. “And they help give context for an important question we have: What’s the big difference between people who respond and people who don’t?”
The microbiome, of course, is inordinately complex — with trillions of bacteria working in tandem to produce multivariate responses. It’s important not just to have a diverse microbiome, but to have the right cocktail of bacteria.
For example, a study published Wednesday in npj Biofilms and Microbes found that certain chemotherapies used to treat metastatic colorectal cancer actually become toxic to patients in the presence of certain gut bacteria. And another Science study, published this September, found a bacteria that often lurks in pancreatic tumors can actually break down chemotherapy — making it wholly ineffective.
That raises important questions:
“Should we be profiling the gut microbiome in cancer patients going into immunotherapy?” said Dr. Jennifer Wargo, a researcher at MD Anderson Cancer Center who led one of the Science studies published Thursday. “And should we also be limiting, or closely monitoring, the antibiotic use in these patients?”
“Should we be profiling the gut microbiome in cancer patients going into immunotherapy?”
Dr. Jennifer Wargo, lead researcher
Wargo’s study isolated two bacteria that help buoy PD-1 immunotherapy response in metastatic melanomas. The researchers collected oral, gut, and fecal microbiome samples — along with tumor biopsies — before and after therapy. After treatment was complete, they divided the patients into “responders” and “non-responders,” and profiled each microbiome with genetic sequencing.
“What we found was impressive: There were major differences both in the diversity and composition of the gut microbiome in responders versus non-responders,” Wargo said. Those who did well had greater bacterial diversity in their gut, whereas those whose tumors didn’t much shrink had fewer varieties of microbes present.
Furthermore, responders to the immunotherapy had a far greater density of killer T cells — which are largely responsible for attacking cancer. The researchers found that the presence of the Faecalibacterium and Clostridiales bacteria seemed to account for the difference in T cell density.
And sure enough, when these bacteria were given to cancer patients via a fecal matter transplant, they were more likely to respond to treatment and live longer without their tumor recurring or worsening.
When the microbes found in responding patients were transplanted into mice whose microbiomes had been completely depleted, they responded in a similarly positive manner to immunotherapies.
Wargo cautioned, however, that this data should be approached with care. Any given bacteria might help one cancer and its associated immunotherapy — but its presence might adversely affect a patient dealing with another disease and a different drug.
“If you’re changing the microbiome, depending on how you do it, it may not help you — and it might harm you,” she said. “Don’t try this at home.”
“If you’re changing the microbiome, depending on how you do it, it may not help you — and it might harm you. Don’t try this at home.”
Dr. Jennifer Wargo
The second Science study that’s out Thursday also studied a PD-1 inhibitor immunotherapy, but in patients with kidney and lung cancer. The study, led by Laurence Zitvogel, scientific director of the Gustave Roussy Cancer Center in France, found that patients who had taken antibiotics recently — for urinary tract infections, for instance — had lessened survival rates when compared to those who had not.
After analyzing the participants’ microbiomes, the researchers found that a bacterium called Akkermansia muciniphila was linked to strong clinical outcomes. And when that bug was implanted into microbiome-depleted mice, their immune systems ramped up and they responded better to therapy.
“This does have to be read with caution, however,” said Romina Goldszmid, head of inflammatory cell dynamics at the National Cancer Institute who was not involved in the study. “If there’s a link between the microbiome and response to immunotherapy, by no means should we interpret that as ‘stop antibiotics.’”
Instead, she called for further studies into the mechanistic relationship between bodily flora, cancer cells, and the drugs designed to kill them.
It’s still not understood why, exactly, the presence of “good” bacteria helps buttress the body’s immune system. There are theories, however: Perhaps the “good” bacteria produce certain molecules linked to metabolism that help immune cells proliferate. Other, “bad” bacteria might excrete metabolites that impair systemic immunity.
“This is all very context-specific, and multiple different factors need to be considered on how best to change the microbiome,” Wargo said. When it comes to optimizing cancer therapy, she said, treatments will have to be heavily personalized, based on what a patient’s gut microbiome looks like already.
“This won’t be a ‘one bug, one drug’ approach,” Wargo said.