“We started Moonshot a little over 5 years ago with the intention of ending the pain and suffering of patients with cancer, and we have really made a lot of progress,” Wargo said. “We have focused on some of the known strategies for improving responses, but then we found this novel way that you could potentially impact patient response to cancer therapy using very different approaches—namely, the gut microbiome.”
First of its Kind
For the study, the MD Anderson researchers focused on patients with metastatic melanoma treated with anti-PD-1 checkpoint blockade.
Based on an analysis of fecal samples used to assess microbiomes from patients who responded to immunotherapy and some who did not, the researchers showed patients had their disease controlled longer if they had more diverse bacteria or an abundance of certain bacteria in their gut.
“We found that patients who had a higher diversity of bacteria within the gut microbiome had better responses [to immunotherapy], and then there were also differences in the composition,” Wargo said. “Patients who had higher diversity of the Ruminococcaceae bacteria had better responses, whereas those who had a higher abundance of the [Bacteroidales] had worse responses.”
Ruminococcaceae is the most common order of bacteria in the digestive tract where they break down complex carbohydrates, including plant material, while helping maintain gut health (Diversity 2013; 5(3):627-640). Bacteroidales are the most abundant of the cultured gram-negative organisms in the human colonic microbiota, and also are among the most important periodontal pathogens (J Bacteriol 2008;190(2):736-742).
To assess the impact of the microbiome, the researchers analyzed both tissue samples from inside the cheek (buccal) and fecal samples of patients treated with anti-PD-1 therapy. They then used 16S rRNA and whole genome sequencing to determine the diversity, composition, and functional potential of the microbiomes.
While no substantial differences in immunotherapy response or tumor progression were seen in the buccal samples, the fecal samples would help validate the gut microbiome as a predictor of patients' responses to cancer therapy.
According to the researchers, patients with high diversity of bacteria in their digestive tract had longer median progression-free survival (PFS). While more than half did not see their tumors progress in the patient group with high diversity, those with intermediate and low diversity had median PFS of 232 and 188 days, respectively.
The study also showed patients with high levels of the beneficial Ruminococcaceae had greater T-cell penetration into tumors and higher levels of circulating T cells that kill abnormal cells, according to the researchers. Those with abundant Bacteroidales, meanwhile, had higher levels of circulating regulatory T cells, myeloid-derived suppressor cells, and a blunted cytokine response, weakening anti-tumor immunity.
In many ways, the MD Anderson team's research supported previous preclinical studies of the gut microbiome, Gopalakrishnan said.
“I think our findings were actually quite in line with what others had seen in preclinical studies. The diversity-associated response had already been proven in the context of people with cancer and undergoing immunotherapy. And we also expected to see some compositional differences,” he explained.
A subsequent fecal transplant mouse study conducted to indentify casual mechanisms for the gut microbiome's ability to enhance response to cancer therapy yielded significant new data, however.
“I think one of the most striking things about the study was that we took stool from patients who had responded and from patients who were not responsive and inserted them into germ-free mice,” Gopalakrishnan said. The mice that received transplants from responding patients generated an abundance of Ruminococcaceae bacteria and saw significantly reduced tumor growth, higher densities of beneficial T cells, lower levels of immune-suppressive cells, and also had better outcomes when treated with immune checkpoint blockade, he explained.
“There was a lot of excitement, and skepticism, about the mouse study because preclinical studies had already shown it was possible to change their microbiome to make their responses better,” Wargo added. “And so it really wasn't until we were able to validate it in patients that it made the scientific and medical communities perk up a little bit and say, ‘Hey. This is real!’”
Another of the study's striking findings, Wargo said, was that the right bacteria in the gut microbiome actually increased antigen processing and presentation by the immune system at the tumor site.
“I have been studying biomarkers and response to immunotherapy for years and years. And really, the ones we have seen have been relatively modest in their ability to predict who will respond,” she said. “But when you look at the association, or the signal of the gut microbiome, and compare it with other biomarkers, it's actually quite strong.”
One of the “unintended consequences” of the published study is the added excitement about probiotics, Wargo said.
“There's really a lot of excitement about this, and I think that people are now very enthusiastic about the notion that we could just change the microbiome and potentially enhance responses, but it's tricky. We're not sure exactly how to do that just yet,” she explained.
Wargo urges patients, especially those with cancer and about to go on immunotherapy, to proceed with caution before buying off-the-shelf probiotics promising to improve their immune system.
“We are all pretty confident that a strategy modulating the microbiome can actually enhance therapeutic responses,” Wargo said. “But I think also all of the experts agree that we don't know how best to do that just yet. So patients really need to work with their treatment team to look closely at whether they should be changing their diet when they are being treated. In fact, some preclinical studies have shown probiotics may actually harm a response to immunotherapy.
“Can we change the microbiome and make responses better to cancer therapy?” Wargo asked, rhetorically. “Well, I know I am an optimist, but the answer is a resounding, ‘Yes!’ I have no doubt that it will help. But how we do it is really critical. Because, by doing things to change the microbiome, you could help; but you may not help and you could even harm a response.”
Another clinical implication of the gut microbiome study findings is whether it is time to begin profiling the gut microbiome in patients with cancer going onto immunotherapy to try and enhance their response to treatment, Wargo said, noting several companies launched recently to offer those very services.
”I think that it will help us to guide patient care, but it is not ‘everything,” she said. “We still need to take other things into account like, ‘What are the mutations within in the tumor itself?’ And, ‘What other factors are there that could be contributing to response?’”
To try to find the answers to those research questions and more, the MD Anderson researchers are collaborating with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics to design and run a clinical trial that will test the hypothesis that changing the microbiome can actually enhance responses to therapy.
“We're finalizing the design of that now, but basically we are going to be taking patients with metastatic melanoma who are going on to treatment with anti-PD-1, and then treating them either with a live bacterial product or with a fecal transplant to attempt to change the microbiome,” Wargo said. “We are going [to be asking], ‘How safe is this? How can we actually change the microbiome?’ And also, of course, we'll be looking at responses and immune cells within the tumor as well as other metrics,” she explained.
“It's very exciting! I think, certainly, there is tremendous interest: patients want to sign up for these trials. So, the key is going to be working together to do this,” Wargo concluded. “Right now, we don't know what the perfect microbiome is to give to patients to make them complete responders to cancer therapy, but we're working on it.”
Chuck Holt is a contributing writer.Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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