Harnessing the Power of Microbes to Fight Cancer

Jasenka Piljac Zegarac, PhD

October 25, 2019

Probiotics, traditionally perceived to be good for the gut and overall health, may not be the best choice in patients with cancer. The surprising preliminary findings of a recent study in patients with melanoma indicate that users of over-the counter (OTC) probiotics have one-third the odds of responding to immunotherapy treatment with anti-programmed cell death-1 checkpoint inhibitors compared with patients not taking probiotics.

"What we found is that patients who are taking probiotics have decreased diversity of the microbiome, a key measure of overall gut health, and seem to have a decreased response to immunotherapy," said Jennifer McQuade, MD, MS, MA, LAc, medical oncologist with the University of Texas MD Anderson Cancer Center in Houston.

While such a dramatic decrease in the efficacy of immunotherapy in probiotic users may come as a surprise, a close link between the gut microbiome composition and the efficacy of cancer therapies has already been established in numerous human and animal studies. Microbiome patterns associated with improved response to cancer immunotherapies have been identified, prompting researchers to more closely examine the microbiome signatures of individuals who responded to treatment.

As the science on this topic continues to emerge, both clinicians and patients are left wondering whether interventions into the microbiome can increase the chances of a positive outcome.

Probiotics Popular Among Patients With Cancer, Despite Unclear Value

McQuade said that questions related to probiotic use come up frequently in her discussions with patients. In fact, these discussions prompted her and her colleagues Christine Spencer, PhD, from the Parker Institute for Cancer Immunotherapy (PICI), and Jennifer Wargo, MD, MMSc, a PICI investigator at MD Anderson Cancer Center, to conduct that recent study in patients with melanoma, which more closely examined the use of probiotics. Their findings indicate that at the initiation of cancer therapy, a significant number of patients are already taking OTC probiotics.

"We found that 42% of our patients use OTC probiotics, which is probably the result of people reading about the gut microbiome's influence on immunotherapy response and hoping that a probiotic pill is an easy way to manipulate it," said McQuade.

Although this was not a controlled study, and patients took unselected probiotics, the findings pointing to decreased microbiome diversity in probiotic users were in line with an earlier study showing impaired microbiome reconstitution due to probiotic use.

"This is basically competitive exclusion at play, where you are overwhelming the system with a few strains of bacteria and damaging the overall healthy ecosystem," she continues. "I now ask my patients about probiotic use and, if they are using probiotics, I specifically ask them to discontinue."

Tessa M. Andermann, MD, MPH, assistant professor in the Division of Infectious Diseases at the University of North Carolina, Chapel Hill, agreed that special consideration is needed in immunocompromised patients.

"Probiotics remain too much of an unknown entity, especially in patients with compromised immune systems, and there is not enough data demonstrating safety and efficacy to warrant the potential risk of infection," she said. "We have seen bloodstream infections of those same organisms used in probiotics in hospitalized patients."

Boosting Gut Microbiome Diversity via Other Means May Reap Benefits

In addition to probiotics, patients often ask their providers about alternative ways of modulating the gut microbiome using prebiotic fibers or other specific dietary interventions.

But how safe and effective are they?

Prebiotic fibers, such as fructo-oligosaccharides (FOS), are used as substrates by specific species of the gut microbiota to produce short-chain fatty acids, which in turn play an important role in immune homeostasis and maintaining the integrity of the intestinal epithelium.

Andermann explained that, as with probiotics, the safety of prebiotics has not been adequately established in patients with cancer or those who have undergone transplantation. Furthermore, it is not known whether bacteria that digest these fibers are present in the gut of patients who have received antibiotics and/or chemotherapy.

Andermann and her colleagues conducted a small pilot trial of patients undergoing hematopoietic cell transplantation to determine the maximum tolerated dose of FOS.

"It appears that FOS is well-tolerated, although the microbiome data are still being analyzed," she said.

When McQuade and colleagues analyzed the connection between dietary fiber and response to immunotherapy in a subset of patients with melanoma who consumed a fiber-rich diet, the findings were eye opening.

"Patients who were eating a higher-fiber diet had an increased abundance of pro-response bacteria, and our preliminary data shows that they were about five times more likely to respond to immunotherapy," she said.

To further investigate the connection between a high-fiber diet and immunity, McQuade and collaborators plan to conduct a controlled feeding study in which study participants will be provided with all their meals, containing 50 g of fiber per day or a control healthy diet with 20 g of fiber per day, over 12 weeks. They will monitor participants' gut microbiomes as well as measures of systemic and antitumor immunity during the study to test whether diet change can shift the gut microbiome and affect immune function. The dietary plan for the study was developed by a registered dietitian who is also a professionally trained chef.

"We are currently conducting a pilot study in melanoma survivors, and at the beginning of next year we will be doing it in cancer patients receiving immunotherapy here at MD Anderson," she said. "Because we can't feed the world, the eventual goal would be to provide guidance to patients about how to best change their eating habits."

In the interim, McQuade counsels her patients to eat a healthy, plant-based, fiber-rich diet — the same one that is recommended by the American Cancer Society for patients with cancer. Again, she stresses the importance of diversity and incorporating lots of different fruits and vegetables, whole grains, and beans, which are a great source of fiber.

Ameliorating Treatment-Induced Gastrointestinal Symptoms

Treatment-induced gastrointestinal symptoms, due to chemotherapy, immunotherapy, or antibiotic use, are common in patients with cancer. Studies have shown that probiotic supplementation can have beneficial effects on acute chemotherapy-related diarrhea as well as on bothersome bowel symptoms in colorectal cancer survivors; however, probiotic use was also associated with impaired postantibiotic gut microbiome reconstitution in mice and variable mucosal colonization in humans.

Andermann noted that probiotics have not been approved by the US Food and Drug Administration as therapy and that OTC formulations vary in both composition and viability. She believes that the variations in probiotic species and dose, as well as host variability, likely contribute to conflicting literature reports about their utility.

"Colonization, whether temporary or persistent, appears to be important for the effectiveness of the probiotic," she said. "However, the gut microbiome of some people may resist colonization of the probiotic, whereas in others, colonization can more easily occur."

In line with her earlier recommendations, McQuade believes the best way to reconstitute the gut microbiome after antibiotic treatment is through diet.

"If you need an antibiotic, you've got to take it," she said. "[After treatment], give it some time, and as you're able to tolerate it, get back on a nice, healthy diet to feed those good bacteria and allow them to grow."

Looking for the "Microbe Pill"

Although clinicians largely agree about the benefits of a fiber-rich diet, the sources and types of fiber needed for a diverse microbiome remain to be identified and verified in clinical studies. In addition, a several-months-long dietary intervention may not be a practical solution for a patient with cancer whose treatment is extremely time sensitive.

The urgency and unmet need that exist in this space are increasingly being recognized. Seres Therapeutics, a Massachusetts-based biotech focusing on microbiome therapies, is collaborating with MD Anderson Cancer Center to develop one of the first biologically derived microbiome therapies for patients with cancer. SER-401, a pill containing a consortium of bacteria associated with improved response to checkpoint inhibitor therapy and manufactured from the microbiome material of healthy donors, is designed to modify the patients' immunologic activity and improve response to checkpoint inhibitor therapy. A simpler way to describe it is targeted therapy for the microbiome of patients with cancer.

"Our interest in the microbiome was catalyzed by a paper published by Dr Jennifer Wargo of MD Anderson Cancer Center that illustrated a signature in the microbiome of patients [with metastatic melanoma] who had a response to checkpoint inhibitor therapy," said Eric D. Shaff, chief executive officer of Seres. "What was particularly interesting in this analysis was the identification of spore-forming Firmicutes in the signature — a group of bacteria that are human gut commensals and for which we at Seres have developed extensive scientific knowledge and unique manufacturing expertise."

In designing SER-401, Seres and MD Anderson Cancer Center investigators more closely examined the microbiome signature that differentiates the patients who responded from those who did not respond to treatment with checkpoint inhibitor therapy. Whole metagenomic shotgun sequence data were obtained from humans and analyzed alongside functional information for a library of commensal microbes maintained by Seres to identify with greater specificity the differences between responders and nonresponders.

"We were able to dial-in the microbiome signature and identify a subset of specific phylogenetic groups of spore-forming bacteria within Ruminococcaceae, a family of Firmicutes, that are associated with improved response. From these data, we can develop a drug that contains the specific signature," explained Matthew Henn, PhD, chief scientific officer at Seres.

The fecal material of healthy donors is screened, and bacterial spores are fractionated during formulation of SER-401, but only if the material meets the predefined microbiome profile, he adds.

A phase 1b clinical trial (MCGRAW) designed to evaluate the safety and tolerability of SER-401 in combination with nivolumab in patients with unresectable or metastatic melanoma is recruiting patients. The trial is sponsored by PICI and conducted in collaboration with Seres and MD Anderson Cancer Center, as well as five other clinical sites across the United States.

"We are guided by data and very optimistic about how the microbiome could be impactful to patients with cancer, but we still have a long way to go," said Shaff. "I think that we will learn a lot [from this trial], which will certainly inform how we think about a path forward."

Earlier this year, Seres also announced a 3-year research collaboration with AstraZeneca. The partnership is expected to tap into the expertise and resources of both companies to bring forward new microbiome-based therapeutics that may increase the efficacy of cancer immunotherapies.

"We are primarily interested in understanding the role of the microbiome and its impact in signaling host immunity and modulating host inflammation, both locally, in the gut, and systemically," said Henn. "We seek to improve our understanding of the cancer types and patient subpopulations most amenable to microbiome intervention and unravel the immune pathways that microbes modulate to improve response. From these insights, we will design future therapeutic candidates."

If these and similar research efforts bear fruit, clinicians may one day be able to positively manipulate the microbiomes of patients with cancer using their prescription pads. In the meantime, experts largely agree that a healthy, fiber-rich diet is a good approach to achieving a diverse and healthy microbiome.

"The general advice to incorporate healthy fruits, vegetables, and grains into one's diet remains good sound advice while we look to improve our understanding of how we might be able to alter the microbiome to improve health," concluded Andermann.

Jasenka Piljac Zegarac, PhD, is a freelance science/medical writer with more than 15 years of hands-on scientific research experience. She covers trending topics in medicine, science, and food/nutrition and regularly contributes to several professional publications, online medical publishers, and trade journals.

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