With the recent breakthroughs in immunotherapy, treatments that modulate the immune system are now being used across numerous cancer types and across the spectrum of disease with significant success, but not all patients achieve objective responses. There is still a critical need to better understand which patients will benefit from therapy as well as the proper timing, sequencing, and combination of different therapeutic agents.

At the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium, experts in the fields of genomics, genetics, and infectious diseases discussed the role of the gut microbiome in cancer immunotherapy and efforts to modulate this environment to enhance treatment responses.

“There is increasing evidence for the role of the microbiome in health and disease, with data showing that microbes can actually influence overall immunity as well as responses to cancer therapy,” said Jennifer Ann Wargo, MD, MMSc, Associate Professor of Genomic Medicine and Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston.¹ “These microbes within tumors in the gut can actually serve as a biomarker of response to cancer therapy. They can also potentially be targeted, and efforts are underway to modulate microbes to enhance responses to cancer therapy.”

Understanding the Role of the Microbiome

As Dr. Wargo explained, there are more than 100 trillion microbes in the human body—outnumbering normal cells by up to a factor of 10—and a large proportion of these microbes are in the gut. Disturbances of the gut microbiome have been associated with a number of different diseases, ranging from inflammatory bowel disease to asthma, eczema, and even colon cancer.

There is increasing evidence for the role of the microbiome in health and disease, with data showing that microbes can actually influence overall immunity as well as responses to cancer therapy.

— Jennifer Ann Wargo, MD, MMSc

Tweet this quote

More recently, researchers have demonstrated an association between the diversity of the gut microbiome and differential outcomes in the setting of stem cell transplantation in patients with hematologic malignancies.² The composition of the gut microbiome has also been linked with differential responses to checkpoint blockade in murine models.³

Based on this evidence, Dr. Wargo and colleagues sought to understand the role of the gut microbiome in response to checkpoint blockade in patients with melanoma. Led by Deepak Gopalakrishnan, PhD, the researchers performed microbiome sequencing and immune profiling on oral and fecal microbiome samples in a large cohort of patients with metastatic melanoma who were about to start therapy.

“Right off the bat, we found that patients who responded to anti–programmed cell death protein 1 (anti–PD-1)-based therapy had a higher diversity of gut bacteria and compositional differences associated with prolonged progression-free survival,” said Dr. Wargo. “Importantly, immune profiling showed that these favorable signatures were actually associated with enhanced immune responses in the tumor microenvironment.”

Researchers performed a fecal microbiota transplant from either responding or nonresponding patients into germ-free mice that were then implanted with melanoma tumors and treated with checkpoint blockade. The results suggested that it was possible to modulate the gut microbiome to enhance responses to immunotherapy.

“In mice that received a fecal transplant from a nonresponding patient, tumors grew rapidly and failed to respond to treatment with checkpoint blockade, whereas in mice that received a responder fecal transplant, the tumors grew slowly or were outright rejected, and they responded brilliantly to blockade,” said Dr. Wargo.

Enhancing Responses to Immunotherapy

In patients with both Clostridium difficile infection and irritable bowel syndrome, fecal transplants from healthy donors have been used successfully. Now, given data that suggest a relative dysbiosis in the setting of melanoma and other cancers, several trials are underway to modulate the microbiome in combination with immune checkpoint blockade. However, identifying an optimal consortia of microbes that can enhance responses to immunotherapy remains a challenge, said Dr. Wargo. Although published studies have helped to identify potential signatures, there is not a huge overlap between cohorts that have responded to immunotherapy.

According to Dr. Wargo, there are several factors that can account for these differences, including different methods used for analysis and regional and dietary influences. In addition, the function of these different taxa may be much more important than the phylogeny.

“It’s not the names of the bacteria that matter; it’s what they’re doing,” she explained. “I think results from additional cohorts as well as these fecal transplant trials will help inform an optimal consortium—the secret sauce of microbes.”

Finally, said Dr. Wargo, there is recent evidence that changes in diet can have an impact on gut microbes and associated physiology in a short time frame. Dr. Wargo and colleagues observed that patients on a high-fiber diet had a higher diversity in the gut microbiome, with a higher abundance of favorable taxa.

Although patients with a favorable signature and a low-fiber diet were reasonably likely to respond to anti–PD-1 therapy, those with a favorable signature and a high-fiber diet were nearly nine times as likely to respond to the same treatment. Based on this evidence, the researchers are designing and running dietary intervention trials to test the impact of gut microbes on therapeutic response.

One of the Hottest Research Topics in Cancer

While efforts are underway to modulate microbes to enhance responses to cancer, the optimal means to do so remain incompletely understood. Moreover, said Dr. Wargo, development of these optimal strategies is going to depend not only on a deep mechanistic understanding of how these microbes influence therapeutic responses, but also a comprehensive appreciation of all the factors that influence these microbes.

Microbes are absolutely necessary for proper development and function of the entire hematopoietic system, so it stands to reason that there is a strong relationship between the microbiome and immunologic training and tolerance.

— Ami S. Bhatt, MD, PhD

Tweet this quote

Given the number of questions that remain and the implications for the field, it should not be surprising that the microbiome has become a huge area of interest for researchers. Ami S. Bhatt, MD, PhD, Assistant Professor of Hematology and Genetics at Stanford University School of Medicine, California, reported that more than 30,000 microbiome manuscripts have been published as of 2016, with the past decade exhibiting exponential growth.⁴

“If you compare interest in this topic to others in the field such as cancer genomics or the famous oncogene KRAS,” said Dr. Bhatt, “you can see that the microbiome is arguably quantitatively hotter than even cancer genomics.”

This research represents a major shift in thinking about the treatment of cancer. According to Dr. Bhatt, data from the Center for International Blood and Marrow Transplant Research have shown that only 37% of patients who die in the first year after transplant die of their primary disease, whereas the remaining 63% die of something else.

“We have spent a disproportionate amount of our effort actually focused on the cancer, but if we zoom in on these non–relapse--associated outcomes, many of them have been shown to be associated with the microbiome,” said Dr. Bhatt. “Microbes are absolutely necessary for proper development and function of the entire hematopoietic system, so it stands to reason that there is a strong relationship between the microbiome and immunologic training and tolerance.”

As Dr. Bhatt explained, the basic idea is that in individuals who undergo a lot of treatment with chemotherapeutic agents and other antimicrobial agents, the gut microbiome can end up being dysbiotic. This can lead to selection of pathogens that can then translocate into the bloodstream and cause non–cancer-related adverse outcomes for patients. Proving this theory in the future, however, will require the collection of many types of data and assays as well as better in vitro modeling of the microbiome.

“We’ll need to leverage advanced genomic methods, such as long-read sequencing and single-molecule sequencing, proteomics, and long-range phasing, measuring actual metabolites, not just microbes,” said Dr. Bhatt. “By bringing all of these things together, we’ll be able to better understand what the compounds and molecules are that are actually mediating some of the effects that we think the microbes have on host biology and cancer biology.”

Still at the Bench or Ready for the Bedside?

Despite theenthusiasm for microbiome research, Tessa Andermann, MD, MPH, an infectious diseases fellow at Stanford University School of Medicine, cautioned restraint in interpreting current data.⁵

“There is the potential to use the microbiome as a therapy or prognostic or diagnostic tool, but it’s also important to turn a critical eye to these therapies,” said Dr. Andermann, who conducted a systematic review of studies looking at microbiome-based therapeutics in patients with cancer.

There is the potential to use the microbiome as a therapy or prognostic or diagnostic tool, but it’s also important to turn a critical eye to these therapies.

— Tessa Andermann, MD, MPH

Tweet this quote

According to Dr. Andermann, pilot studies of fecal microbiota transplant in patients with steroid-refractory or -resistant gastrointestinal graft-vs-host disease showed “impressive complete remissions,” considering typical outcomes for this population. More than 50% of these patients experienced remission of their graft-vs-host disease as a result of fecal transplant.

“In steroid-refractory gastrointestinal graft-vs-host disease, 90% to 100% of patients will usually die,” said Dr. Andermann. “Even though these studies had a small number of patients, it gives me hope to see that quite a few patients were alive 6 months after severe steroid-refractory graft-vs-host disease.”

Nevertheless, there is currently no standardized protocol for fecal microbiota transplant. Recommendations from the U.S. Food and Drug Administration (FDA) differ significantly from European consensus guidelines, said Dr. Andermann, who emphasized that these procedures are not for immunocompromised patients.

“The recommendations are specific to immunocompetent patients who generally have C difficile infection,” she observed. “We really have no guidelines for fecal microbiota transplant in immunocompromised patients.”

Are Probiotics Safe?

Lack of knowledge about the so-called secret sauce of microbes—the optimal microbial consortium—has not stopped patients from attempting to modulate their own microbiome with over-the-counter probiotics. The few clinical trials that have looked at outcomes in patients with cancer taking probiotics, however, suggest that safety may be an issue.

In one study, a probiotic regimen of Lactobacillus rhamnosus GG—a strain of L rhamnosus isolated in 1983—after allogeneic hematopoietic stem cell transplant did not appreciably alter the gut microbiome.⁶ What’s more, 40% of patients in the probiotic group developed chronic graft-vs-host disease compared to 18% in the control group.

“There are big concerns about the potential risks of probiotics in patients with cancer, and there is a lack of data demonstrating safety,” said Dr. Andermann. “What we know right now is that adverse events are extremely underreported.” According to Dr. Andermann, probiotics are known to cause infection, and if the infection is antibiotic-resistant, clinicians can have a much harder time treating the patient. Probiotics are also unregulated by the FDA.

“There’s no consensus about dosing, the correct duration, or even the species or strain of probiotic to use,” said Dr. Andermann. “Clearly, there needs to be more regulation if we’re going to be giving these preparations to our patients with cancer, in order for us to really understand the clinical impact. Given the limited data available, the risk far outweighs the benefits.”

The other experts on the panel were in agreement. As Dr. Wargo reported, an examination of a cohort of patients with metastatic melanoma in her lab found that those who reported taking probiotics had a much less diverse microbiome and were actually less likely to respond to anti–PD-1 therapy.

“This has real potential implications,” said Dr. Wargo. “Careful consideration must be taken by clinicians and patients, as some probiotics may not help and could potentially be harmful.”

“I think the jury is still out,” Dr. Bhatt added. “My strong recommendation to patients is that they not take probiotics because we don’t know what’s in them, and we have no idea what the impact will be on their outcomes.”

Finally, researchers are investigating the clinical utility of prebiotics, which are the indigestible fibers that serve as the primary nutrition source for the commensal organisms in our gut. Drs. -Andermann and Bhatt, as well as Andrew Rezvani, MD, at Stanford recently completed a single-arm dose-escalation trial of fructooligosaccharides in allogeneic transplant patients. The researchers are currently sequencing the stool samples and analyzing blood samples to determine the best dose of fructooligosaccharides to possibly reduce the incidence of graft-vs-host disease in patients with blood cancer undergoing donor stem cell transplant. ■

DISCLOSURE: Dr. Wargo is on speakers bureaus for Imedex, Dava, Omniprex, -Illumina, and BMS; is on advisory boards for Roche/Genentech, GSK, Novartis, and AstraZeneca; has received clinical trial support from Roche/Genentech, GSK, BMS, and Novartis; is a consultant/scientific advisor to Microbiome DX; and is the co-inventor on a patent submitted by The University of Texas MD Anderson Cancer Center to the U.S. Patent and Trademark Office based on this work. Dr. Bhatt is an advisory board member of Arc Bio, January.ai, and Caribou Biosciences; is a consultant for Kaleido Biosciences and Janssen Human Microbiome Institute; has received honoraria from Illumina and research funding from Agilent; and is on the board of Global Oncology, Inc, a nonprofit organization. Dr. Andermann reported no conflicts of interest.

REFERENCES

1. Wargo JA: Modulating the gut microbiome to enhance responses to immunotherapy. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Presented March 2, 2019.

2, Taur Y, Jenq RR, Perales MA, et al: The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124:1174-1182, 2014.

3. Sivan A, Corrales L, Hubert N, et al: Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084-1089, 2015.

4. Bhatt AS: From precise microbial genomics to precision health: Targeting the gut microbiota in hematologic malignancies. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Presented March 2, 2019.

5. Andermann T: Microbiome manipulation in cancer: Still at the bench or ready for the bedside? 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Presented March 2, 2019.

6. Gorshein E, Wei C, Ambrosy S, et al: Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation. Clin Transplant 31(5), 2017.