Harnessing the gut to improve cancer outcomes
The gut microbiome — made up of more than a trillion microbes, archaea, viruses, phages, yeast, fungi and bacteria in the intestine — has long been linked to a variety of issues across medical disciplines, from mental health to digestion, allergies and immune function.
Data now are linking a healthy gut microbiome to improved responses to immunotherapy for patients with melanoma, and researchers are just starting to learn how a healthy microbiome could influence responses to treatment across multiple tumor types.
“We have trillions of microbes in our body, and the largest proportion of these reside in the gut,” Jennifer Wargo, MD, MMSc, professor in the department of surgical oncology and genomic medicine at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “Microbes do not just help us digest food; they interact with our immune system constantly. On one side there are trillions of microbes, and on the other side there is a dense network of immune cells, which feed a constant to-and-from and an education of the immune system by those microbes in the gut.”
A healthy microbiome may indicate a healthy immune system and, in turn, better response to immunotherapy among patients with cancer, Wargo said.
“But, on the other hand, if you have a dysfunctional gut microbiome, then your immune system doesn’t work well and you are unable to respond to immunotherapy,” she said.
Early research has suggested that alterations to the gut microbiome through fecal microbiota transplants may improve responses to immunotherapy among patients who have refractory disease.
Fecal transplants, however, have come under scrutiny after two immunocompromised adults who received them developed invasive infections caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. One of the individuals died.
HemOnc Today spoke with oncologists, immunologists and microbiologists about how the gut microbiome might impact response to cancer treatment; the utility and safety of fecal transplants, especially as a means to prevent graft-versus-host disease; and how monitoring and manipulation of the gut microbiome may become a key aspect of cancer treatment in the future.
A healthy microbiome
The first thing to know about the gut microbiome, according to researchers, is that there is no standard definition of a “healthy” microbiome or its composition.
One of the only guides to gut health is making sure it has a large sample of different microbes.
“We don’t know what a fully healthy microbiome looks like,” Jeremy Burton, PhD, BSc, MSc, dBA, microbiologist at Lawson Health Research Institute in Canada, told HemOnc Today. “A healthy microbiome in North America may be different than a healthy one in Africa, where people have different diets.”
A healthy microbiome may include different microbes depending on the individual and could influence responses to certain therapies based on the bacteria living inside the intestine.
“People get confused because the same microbes don’t always show up in research studies profiling the microbiome; but it’s not necessarily the names of the different microbes, it’s their function and what they are doing that really matter,” Wargo said. “Having a healthy gut microbiome that improves the immune system by direct interaction with the gut or by producing metabolites that increase immunity is how these bugs in our gut are shaping our overall immune system and response to immunotherapy.”
Research suggests an unhealthy microbiome — usually defined by a lack of microbe diversity — may be improved with dietary changes or fecal transplants.
Fecal transplants involve taking stool samples from heavily prescreened healthy donors and inserting them into the patient via capsules, colonoscopy or nasoduodenal tube with the goal of diversifying the recipient’s microbiome.
“Fecal transplants have been around for centuries,” Wargo said. “In China, they used what they called ‘yellow soup’ to treat diarrheal diseases. Fecal transplants gained credence in the 1950s, when they were used for Clostridium difficile infection. Now it’s a very effective strategy used in patients with refractory C. difficile infections.”
The practice has not come without controversy, however. In June, the FDA issued a warning on the potential risk for serious or life-threatening infections with the use fecal transplants following infections in two patients caused by multidrug-resistant organisms.
“[We are] informing members of the medical and scientific communities and other interested persons of the potential risk of [fecal transplants] and the resultant serious adverse reactions that may occur,” the FDA wrote as part of the warning. “Patients considering [fecal transplants] to treat C. difficile infection should speak to their health care provider to understand the potential risks associated with the product’s use.”
The transplants used in the two infected individuals were prepared from stool obtained from the same donor.
Still, researchers said that fecal transplants have a potentially important future in the field of cancer treatment if they are used correctly and safely.
“Fecal transplants are a fairly crude methodology at present,” Burton said. “We do a lot of screening to make sure there are noninfectious agents, and it goes even further than that. We have to be very careful in screening all the material — infectious disease, family history, everything — to make sure we are not introducing something harmful to the patients.”
Insights from responders
Studies have sought to characterize the gut microbiome of responders to cancer immunotherapy compared with nonresponders to elucidate how manipulation of the microbiome may improve cancer outcomes.
At MD Anderson Cancer Center, Wargo and colleagues analyzed microbiome samples from 89 patients with melanoma treated with anti-PD-1 immune checkpoint inhibitors — including 54 patients deemed responders and 35 nonresponders 6 months after the start of treatment — to determine whether characteristics of the gut microbiome influenced response.
Researchers collected oral (buccal) and gut (fecal) microbiome samples, as well as tumor biopsies and blood samples, at matched pretreatment time points. They performed taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing on all available oral and gut samples.
Results — published last year in Science — showed that 30 gut samples from patients who responded to immunotherapy had a greater diversity of bacteria in the gut microbiome compared with 13 gut samples from patients who did not respond well to treatment (P < .01). The greater diversity included a higher prevalence of bacteria from the Ruminococcaceae family within the Clostridiales order among responders, whereas nonresponders had a higher prevalence of bacteria within the Bacteroidales order (P < .01 for both).
Results also showed that high gut microbiome diversity appeared associated with longer PFS than intermediate (P = .02) and low (P = .04) diversity.
Cox proportional hazards analyses showed that the best microbial predictors of response to anti-PD-1 therapy were alpha diversity (intermediate, HR = 3.6; 95% CI, 1.02-12.74; low HR = 3.57, 95% CI, 1.02-12.52) and high amounts of Faecalibacterium (HR = 2.92; 95% CI, 1.08-7.89) and Bacteroidales (HR = 0.39; 95% CI, 0.15-1.03) in the fecal microbiome.
“We showed in early studies that there are differences in the diversity and composition of the gut microbiome in responders and nonresponders,” Wargo said. “Patients who had a more diverse microbiome had a much greater chance of responding.
“In addition to diversity, the composition mattered,” she added. “If patients had a higher abundance of specific bacterial taxes, they were more likely to respond.”
After making this connection, researchers sought to determine whether microbiome intervention — such as via diet and lifestyle changes — could impact response to immunotherapy.
In a study presented this year at AACR Annual Meeting, Wargo and colleagues found that patients with melanoma who ate a high-fiber diet had more diverse gut microbiomes and, consequently, had five times greater odds of responding to anti-PD-1 treatment (OR = 5.3; 95% CI, 1.02-26.3).
One surprise was that patients who reported taking over-the-counter probiotics had a less diverse microbiome and about 70% lower odds of responding to immunotherapy.
“It’s not just about the bugs that are there in the microbiome, it’s also about what you are feeding them,” Wargo said. “It was a shock to us when we found that patients who took probiotics actually had a less diverse microbiome. It really calls into question how you modulate the microbiome.”
A phase 1 study led by Saman Maleki, PhD, MSc, tumor immunologist and cancer biologist at Lawson Health Research Institute, is underway to examine whether fecal transplants can improve outcomes among patients with advanced or metastatic melanoma treated with immunotherapy. At the time of reporting, Maleki and colleagues had enrolled two of 20 potential patients for the trial.
“In this trial, we administer the fecal microbiota transplant and let it settle for a week to help the microbiome,” Maleki said. “We then treat patients with anti-PD-1 agents such as pembrolizumab [Keytruda, Merck] and nivolumab [Opdivo, Bristol-Myers Squibb] at a standard treatment level for 2 years.
“We know the response time in the general population is 2 to 3 months, so we are looking to see that type of response here,” he added. “However, the primary endpoint is safety, with the secondary being changes in immune cell populations, gut microbiome and response to treatment.”
The research does not end at melanoma, however. Maleki said the fact that researchers are observing a signal in melanoma indicates that fecal transplants may work in other types of cancer because antitumor immunities are relatively similar across cancer types.
“We are already working on potential trials for renal cancer and lung cancer, and we expect to expand the melanoma trial to phase 2 and get to randomization,” he added. “I can’t speak to the results, but so far we have not seen any problems with the two patients we have been treating.”
Need for high-quality studies in GVHD
Studies also have connected the gut microbiome to outcomes following hematopoietic stem cell transplantation.
“Looking at the gut microbiome in terms of affecting outcomes after allogeneic cell transplants is still relatively new and has been evolving over the last decade or so,” Marco Mielcarek, MD, medical director of adult blood and marrow transplantation at Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, told HemOnc Today. “The data are becoming a little bit more mature, but there are still a lot of unanswered questions.”
For instance, a study presented by Peled and colleagues at ASH Annual Meeting and Exposition last year showed higher gut microbial diversity was associated with improved survival after HSCT.
The analysis included 991 adults who underwent allogeneic HSCT at four international transplant centers. Stool samples from transplant patients showed gut microbiota diversity scores that were 1.7- to 2.5-fold lower than those of healthy volunteers.
Results of those patients treated at Memorial Sloan Kettering Cancer Center showed that high pretransplant microbial diversity was associated with better OS (HR = 0.69; P = .002).
In an expansion of that study by Peled and colleagues — presented last year at BMT Tandem Meetings — researchers found that greater diversity of gut microbiota at the time of neutrophil engraftment after allogeneic HSCT also was associated with better OS.
After analyzing 5,823 serial stool samples from 1,118 patients who underwent allogeneic HSCT at the four centers, researchers identified exposure to piperacillin-tazobactam (P < .01) and low calorie intake (P < .05) as predictors of reduced gut microbial diversity. Samples collected on the days of piperacillin-tazobactam administration showed lower diversity than those collected on days without piperacillin-tazobactam (Simpson reciprocal, 4.15 ± 0.35 vs. 7.75 ± 0.21; P = 1.6-12).
“What has become clear is that diverse communities of bacteria in the gut appear to be beneficial and are associated with better outcomes after transplant,” Mielcarek said. “Causality still needs to be established, but patients who do not have sufficient microbial diversity after transplants have worse outcomes.”
Regimens used to prepare patients for transplant — such as high-dose chemotherapy with or without radiation — as well as a change in diet due to treatment could be affecting the gut microbiome.
“When you have a patient on high-dose chemotherapy, they can no longer eat the way they used to or eat in a way that may be beneficial to maintaining gut diversity,” Mielcarek said.
Studies also have specifically linked the gut microbiome to development of GVHD after transplant.
“In theory, modulating diversity of the microbiome could be used both to prevent and treat GVHD,” Mielcarek said. “High-quality studies are still lacking, but there are some smaller ones that have looked at preventing GVHD and treating GVHD that is resistant to the standard treatment.”
In another study presented at BMT Tandem Meetings, Ponce and colleagues found that a diverse gut microbiome had a local protective effect among patients with nongastrointestinal or upper-GI acute GVHD.
Because the majority of intestinal microbiota live in the colon, researchers theorized that certain features of the microbiota offer local protection of the lower GI tract.
The analysis included 286 patients who underwent allogeneic HSCT and developed acute GVHD by day 100 in the upper GI tract only (n = 105) or lower GI tract with or without upper GI involvement (n = 84), or who had no GI tract involvement (n = 97).
Researchers evaluated 1,994 stool samples — about seven for every patient — 3 weeks before and after GVHD onset. Trends in microbial diversity relative to the day of acute GVHD onset showed distinct dynamics among the three groups.
When researchers grouped samples into pre-onset (day –19 to 0) and post-onset (day 1-20) categories, the microbial diversity in lower GI cases (median, 2.05) appeared significantly lower than that of the upper GI group (median, 2.65) and non-GI group (median, 3.45) prior to acute GVHD onset (P < .05).
The trend became more prominent after acute GVHD onset — lower GI cases had a median diversity score of 3.14 compared with a median diversity score of 5.73 for the upper GI group and 7.2 for the non-GI group (P < .005).
“If these results can be confirmed, one could envision interventions aimed at preventing the loss of diversity, such avoidance of certain types of antibiotics, use of probiotics or controlled oral feeding for patients who would typically only receive parenteral nutrition after transplant,” Mielcarek told HemOnc Today at the time the study was presented. “In my opinion, it needs to be demonstrated, though, that the loss of microbial diversity in patients with lower GI tract GVHD is a cause rather than just the result of GVHD that could have disrupted the mucosal environment certain beneficial bacterial communities depend on.”
Because fecal transplants change the microbiome by adding different bacteria, they also could serve as a treatment for GVHD associated with a lack of diversity in the gut. However, research is still preliminary, and definitive answers could be a long way away when it comes to GVHD, fecal transplants and the gut microbiome, experts said.
“The ultimate gold standard is whether these novel microbiome-altering interventions affect long-term survival,” Mielcarek said in an interview. “Half of the patients who have steroid-refractory GVHD die within 6 months. The transplant community has tried many different treatments, mostly immunosuppressive treatments to improve that dismal outcome, and to the best of my knowledge there is still no effective standard of care that has allowed us to improve this dismal 6-month survival estimate.
“Anything the fecal transplant method can contribute must be compared with survival endpoints 6 months or 12 months down the road,” he added. “The real measure of success is survival after transplant demonstrated in high-quality randomized trials, and we just don’t have that yet.”
Safety moving forward
The use of fecal transplants to change the gut microbiome among patients with cancer will have to overcome any potential stigma instigated by the FDA’s June warning.
“This therapy can work but, as highlighted by the FDA safety statement, it is not without risk and we need to be very careful about how we use these [transplants],” Wargo said.
Researchers said, however, that there are key factors to glean from patients who became ill from the fecal transplants.
First, the two patients cited in the FDA warning were immunocompromised, which has been a disqualifier for patients in cancer studies.
“Health Canada has approved all of the studies we are doing,” Burton said. “When you are giving a microorganism — whether that’s a fecal transplant or yogurt — there is always a risk for infection. We always have to be careful in using these in at-risk populations.”
Second, the donor stool and resulting fecal transplant used in the two individuals was not tested for ESBL-producing gram-negative organisms prior to use, experts said.
“We monitor donors for ESBL, which is the bacteria that caused the infection in those patients,” Maleki said. “Health Canada asked us to send a response to them so they could approve the screening process with us.”
Overall, however, researchers said the use of fecal transplants — and the overall study of the gut microbiome to predict cancer outcomes and improve response to treatment — will be very important and a key topic of research moving forward.
“This area has great potential, and maybe we won’t have to use such crude preparation in the future,” Burton said. “Maybe we could find the few bacteria that are responsible for invoking the responses that we get ... but that’s going to take time and technology upgrades, and frankly we still don’t know if we are changing a few microbes or the whole community.” – by John DeRosier
Gopalakrishnan V, et al. Science. 2018;doi:10.1126/science.aan4236.
Peled JU, et al. Abstract 3. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Peled JU, et al. Abstract 811. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Ponce DM, et al. Abstract 57. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Spencer C, et al. Abstract 2838/24. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.
For more information:
Jeremy Burton, PhD, BSc, MSc, dBA, can be reached at Lawson Health Research Institute, 750 Baseline Road East, Suite 300, London, Ontario, Canada N6C2R5; email: firstname.lastname@example.org.
Saman Maleki, PhD, MSc, can be reached at Lawson Health Research Institute, 750 Baseline Road East, Room A4-102, London, Ontario, Canada N6A4L6; email: email@example.com.
Marco Mielcarek, MD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N. P.O. Box 19024, Seattle, WA 98109; email: firstname.lastname@example.org.
Jennifer Wargo, MD, MMSc, can be reached at The University of Texas MD Anderson Cancer Center, Office MDA FCT17.6060 (Unit 1484), Houston, TX 77030; email: email@example.com.
Disclosures: Wargo reports advisory/consultant roles with Bristol-Myers Squibb, Dava Oncology, Genentech, GlaxoSmithKline, Illumina and Novartis. Burton, Maleki and Mielcarek report no relevant financial disclosures.