Gut Microbiome May Determine Immunotherapy Response

Liam Davenport

November 15, 2016

LIVERPOOL, United Kingdom — The diversity and nature of the gut microbiome in a patient with advanced melanoma may determine how well the patient responds to immunotherapy, say US researchers, adding that the findings point to opportunities to improve the efficacy of treatment.

The new study, presented at the UK National Cancer Research Institute (NCRI) annual meeting in Liverpool, suggests that for patients who receive immune checkpoint inhibitors, those who have certain species of bacteria in their intestines will respond to treatment better than others.

Jennifer Wargo, MD, associate professor, Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, commented in a release: "Not all patients respond to immunotherapy drugs, and it's hard to know who will benefit from the treatment prior to it being given.

"Our research shows a really interesting link that may mean the immune system is aided by gut bacteria when responding to these drugs," she continued. "The gut microbiome can be changed through a number of different strategies, so there is real potential here to modify the gut microbiome to boost an immunotherapy response."

Pippa Corrie, MD, PhD, chair of the NCRI's Skin Cancer Clinical Studies Group and consultant and associate lecturer in medical oncology, Addenbrooke's Hospital, Cambridge, said that gut bacteria "play a vital role in...maintaining the normal function in our immune systems."

She noted: "Gut microbes have been shown to influence the role of conventional chemotherapy, so it's probably not surprising that they impact on response to new immunotherapies being used in the clinic.

"Manipulating the gut flora may be a new strategy to enhance activity of immunotherapy drugs, as well as to manage problematic toxicity in the future," Dr Corrie added.

Studies in Patients With Advanced Melanoma

Building on previous studies in mice, which indicated that changing the type of bacteria in the intestines can improve the response to immunotherapy, Dr Wargo and colleagues studied more than 200 mouth microbiome samples and more than 100 gut microbiome samples from approximately 230 individuals with advanced melanoma.

The majority of patients had received immunotherapy in addition to standard-of-care therapy. Some received treatment in the context of a clinical trial. Response to therapy was measured using CT scans; the Response Evaluation Criteria in Solid Tumors was used to categorize the response to treatment as complete or partial, as well as to categorize the disease as being either progressive or stable.

In examining the patients' microbiome, the team looked at both its diversity and its composition. "The reason to look at the diversity is that there's published literature that appears to suggest that people who have a more diverse type of microbiome do better in response to therapy," Dr Wargo told Medscape Medical News.

She noted that they also used "16s sequencing to look at the relative abundance of different bacterial taxa within responders vs nonresponders to get a deep look at not only how diverse were they but which bacteria there were in responders as opposed to nonresponders."

The results showed a significantly greater diversity of types of bacteria in the microbiome of patients who responded to immunotherapy. There were also significant differences in the type of bacteria found in the gut.

For example, responders had a significantly greater abundance of bacterial taxa of the order Clostridiales, specifically, Ruminococcus spp, compared to nonresponders, whereas nonresponders had a greater abundance of bacteria of the order Bacteroidales.

The researchers also examined biopsy specimens of immune cells within the melanoma tumors. Unsurprisingly, they found that in those patients who responded to immune therapy, immune infiltrate was higher.

When they compared that data with the result for the abundance of bacteria types within the microbiome, they found that there was a strong positive correlation between the number of killer T cells in the tumor and the abundance of Clostridiales bacteria.

Dr Wargo said: "Then we looked at the abundance of Bacteroides, because we know in nonresponders, that was higher, and there was negative correlation, meaning that if you had Bacteroides, you had lower immune cells."

There was no significant difference in mouth bacteria between those patients who responded to immunotherapy and those who did not.

More Study Needed

Although the findings suggest that the gut microbiome could be used to influence response to immunotherapy in patients with advanced melanoma, Dr Wargo cautioned against overinterpreting the result.

She said: "Definitely I think we need to understand this better. What I don't want people to take away is that, 'I should go out and take a probiotic and I'll respond to my cancer therapy better.' We don't know that, and we need to study this carefully in the context of carefully performed trials.

"But I think that's exactly what the next step is: We need to do more research, both in patients and then also in relevant models in mice and other models where we can better understand how the gut microbiome is influencing response to these cancer therapies," she said.

Dr Wargo pointed out that the findings raise a number of questions. She said: "There may be regional differences; so, does the gut microbiome in a patient in Houston, Texas, look the same as the gut microbiome in a patient somewhere else in the United States or anywhere else in the world? Will this hold true in the treatment of other cancers where immunotherapy is being used?"

She added: "We need to work together as a team, as a global community, and learn from each other and work together to better understand it, so we can really advance the field."

Findings Are Not Unexpected

Approached for comment, Jeffrey S. Weber, MD, PhD, deputy director, Laura and Isaac Perlmutter Cancer Center, and professor of medicine, NYU Langone Medical Center, New York City, told Medscape Medical News that "none of this is really unexpected."

He said: "There's always been a feeling that the microbiome has a major impact on how your immune system works, so a lot of people are not surprised by the fact that certain bacterial species may have an effect on the ability to respond to immunotherapy."

Nevertheless, Dr Weber believes that findings from these and other studies "suggest that we should be paying more attention to three things." The first is the potential of the microbiome to serve as a predictor of treatment response. The second is whether the microbiome can be altered to affect response to immunotherapy, "which is probably a much tougher assignment," he noted. The third is what can be learned from the metabolic pathways followed by the bacteria to explain what affects the immune system.

He said: "Those are the three big things, and there's going to be a ton of work in the next 5 years on those topics. [Dr Wargo's] study was important because it was one of the biggest ones yet that's hammering home the message that, yes, there's an impact of the microbiome, and certain species are good and certain species are probably bad for you."

Dr Weber said that the ultimate goal is to be able to have personalized immunotherapy and that the "holy grail is trying to understand what are the factors that impact on your ability to respond to immunotherapy."

He continued: "I don't think we have a perfect handle on that, or even a really good handle on that yet. But we're slowly getting there, and to the surprise of the immunotherapy types, it turns out to be what's in your poop. Are the microbiome people surprised? Not really, but it's not a field that most of us have much experience with."

The research was funded by the Melanoma Research Alliance and by the Melanoma Moon Shot Program at MD Anderson Cancer Center. The researchers and Dr Weber have disclosed no relevant financial relationships.

2016 NCRI Cancer Conference. Presented November 9, 2016.

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