Manipulating Gut Microbiome to Improve Immunotherapy Response

Alexander M. Castellino, PhD

January 10, 2018

The gut microbiome — the microorganisms that populate the gut — is emerging as a potential "biomarker" that may predict response to immunotherapy. And the finding that bacteria in the gut influence the response to immunotherapy opens up intriguing possibilities for manipulating the microbiome in order to improve responses.

Previously published reports have suggested that patients who respond to immunotherapy have a gut microbiome enriched in certain microorganisms, as have new reports of similar findings, in a series of papers appearing in Science.

These studies "demonstrate that patients can be stratified into responders and nonresponders to immunotherapy on the basis of the composition of their intestinal microbiomes, suggesting that microbiota should be considered when assessing therapeutic intervention," comments Christian Jobin, PhD, from the Department of Infectious Disease and Immunology at the University of Florida, Gainesville, writing in an insights article that accompanies the papers.

"An important and clinically relevant issue is whether manipulation of the intestinal microbiome could turn patients that are nonresponsive to immune checkpoint blockade into responders," he added.

This indeed is an intriguing issue.

Lead study author from one of the studies, Jennifer Wargo, MD, from the MD Anderson Cancer Center in Houston, Texas, pointed out: "You can change your microbiome, it's really not that difficult, so we think these findings open up huge new opportunities."

You can change your microbiome, it's really not that difficult. Dr Jennifer Wargo


A person's microbiome is a modifiable risk factor that can be targeted by diet, exercise, antibiotic or probiotic use, or transplantation of fecal material, commented co-lead  author, Vancheswaran Gopalakrishnan, PhD, also from the MD Anderson Cancer Center, in a press statement.

Indeed, these researchers are already designing a clinical trial that combines checkpoint blockade with microbiome modulation.

Already Banking Stools From Patients on Immunotherapy

They are not alone. Another group, headed by Thomas F. Gajewski, MD, PhD, from the University of Chicago, Illinois, is already banking stool samples from patients with cancer who are being treated with immunotherapy. The team is isolating the organism(s) that confer response benefits.

"In addition, we are in the process of organizing a trial where Bifidobacteria are given in capsule along with anti-PD-1 [anti–programmed cell death-1] therapy to determine if populating the gut microflora with beneficial bacterial will enhance response to therapy," Dr Gajewski told Medscape Medical News.

The study from the University of Chicago showed that responders to immunotherapy for metastatic melanoma had a gut microbiome abundant in eight bacterial species.

This study involved 42 patients who were treated for metastatic melanoma with PD-1 antibodies or anti-CTLA-4 therapy. The clinical response was determined in a blinded manner from the biomarker analysis. Sixteen patients responded to therapy and 26 did not. The 38% response rate was in line with published clinical data on anti-PD-1 therapy in metastatic melanoma.

Stool samples from these patients, taken before they started treatment, were analyzed for their microflora using 16S ribosomal RNA (rRNA) gene amplicon sequencing. The team identified operational taxonomic units and matched them to 16S sequences in the National Center for Biotechnology Information database. They further did a shotgun metagenomic sequencing using species-specific quantitative polymerase chain reaction for candidate species that had validated primers.

Immunotherapy responders had a microflora enriched in Enterococcus faecium, Collinsella aerofaciens, Bifidobacterium adolescentis, Klebsiella pneumoniae, Veillonella parvula, Parabacteroides merdae, Lactobacillus species, and B longum. Nonresponders had a microflora enriched in Ruminococcus obeum and Roseburia intestinalis.

Scoring each patient for favorable and nonfavorable microflora, the researchers noted that a beneficial/nonbeneficial ratio greater than 1.5 correlated with a response.

A causal relationship was established in a mouse study. Fecal material from responders and nonresponders was transferred to germ-free mice and was shown to influence tumor growth in a melanoma mouse model: Faster-growing tumors were seen in mice receiving fecal material from nonresponders and slower-growing tumors were seen in mice receiving fecal material from responders. In addition, anti-PD ligand 1 (anti-PD-L1) therapy was efficacious only in mice receiving fecal material from responders but was ineffective in mice receiving fecal material from nonresponders.

Lead investigator Dr Gajewski told Medscape Medical News that although the responses to cancer immunotherapy have been very exciting, the reality is that most patients do not respond to these drugs. "While response may be dictated because of different cancer pathways or inherited genes that regulate the immune response, from the environmental perspective, the gut microflora is emerging as an important facet that governs the immune response of individuals," he noted.

"As a response biomarker, the gut microbiota looks attractive," Dr Gajewski said.   However, he acknowledged that these observations need to be confirmed in independent data sets.  "We are prospectively banking stools from most cancer patients who are treated with anti-PD-1 at our institution," he added.

Another Study, Another Set of Bacteria

The study from MD Anderson Cancer Center, which was first reported last year from a conference, found a different set of bacteria in the gut microbiome of responders to immunotherapy.

In this analysis, Faecalibacterium species were enriched in responders and Bacteroides thetaiotaomicron and Escherichia coli were enriched in nonresponders.

This team had prospectively collected buccal and fecal samples from 112 patients with metastatic melanoma starting treatment with anti-PD-1 therapy. They also did a taxonomic profiling using 16S rRNA gene sequencing on all oral and fecal samples.

Data for 89 patients indicate that 54 were responders and 35 were nonresponders.

The researchers showed that buccal or oral microflora was not significantly associated with response to anti-PD-1 therapy, but gut microflora was.

Of 30 patients who responded to therapy and 13 who did not, progression-free survival (PFS) was longest in patients who had a higher diversity of gut bacteria when compared with those who had an intermediate and low diversity (median PFS was not reached in the higher-diversity group vs PFS of 232 days and 188 days, respectively).

Antibiotics Reduce Clinical Benefits

In a third study, French researchers led by Bertrand Routy, Gustave Roussy Cancer Campus, Villejuif, France, showed that patients who took antibiotics to treat infections during cancer therapy had reduced responses to anti-PD-1 treatment. Earlier results from this study had been presented at a conference and  reported at the time by Medscape Medical News.

This study involved patients with non-small cell lung cancer (n = 140), renal cell carcinoma (n = 67), and urothelial carcinoma (n = 42) who received anti-PD-1 or anti-PD-L1 therapy. Antibiotics had been administered for common indications, such as dental, urinary, and pulmonary infections, within the 2 months before or 1 month after the start of cancer immunotherapy.

PFS and overall survival (OS) were shorter for patients with antibiotic exposure compared with the overall patient cohort or the cohort of patients for individual tumor types. In the entire cohort of patients, median OS was 20.6 months for patients not receiving antibiotics vs 11.5 months for those receiving antibiotics (P < .001). In patients with lung cancer, median OS was 15.3 months for those taking no antibiotics vs 8.3 months for those on antibiotics (P = .001).

Gut microflora determination using metagenomic shotgun sequencing was used to analyze more than 20 million short DNA sequence reads per sample and compare them with a 9.9-million-gene reference catalog. Metagenomic species correlated to responses were displayed as "barcodes" for each patient. Akkermansia muciniphila emerged as the species enriched in patients with a favorable clinical outcome.

"Our findings suggest that the microbiome governs the cancer-immune set point of cancer bearing individuals and offer novel avenues for manipulating the gut ecosystem to circumvent primary resistance to ICI [immune checkpoint inhibitors]," the authors conclude.

Implications for Therapy With Immune Checkpoint Inhibitors

In his insights article, Dr Jobin wonders whether these findings on the relationship between gut microbiome and cancer immunotherapy may eventually "translate to new therapeutics."

He notes the success of fecal transplants in another area: Fecal-microbiota transplantation from healthy donors has provided a 90% clinical response rate in patients with recurrent Clostridium difficile infection, a leading cause of antibiotic-associated diarrhea.

"Synthetic microbial communities could be assembled to optimize patient responses to immunotherapy," Dr Jobin suggests.

However, he also notes that no universal bacterial species has defined response to therapy. Each of the three recently published studies has identified a different set of bacteria, but the divergent observations may be related to type of cancer or patient population, he pointed out.

Dr Gajewski also noted that the method of segregating patients into responders and nonresponders differed across the studies, as did the methods of analysis. "Direct comparison of species identified across the studies should be viewed with caution," he said.

"Detailed mechanistic studies into how bacteria reenergize tumor immune microenvironments will be necessary to fully comprehend this phenomenon," Dr Jobin concludes.

Disclosures for all investigators can be found in the publications. Dr Gajewski has the following disclosures: an advisory board member for Roche-Genentech, Merck, AbbVie, Bayer, Aduro, and Fog Pharma; research support from Roche-Genentech, BMS, Merck, Incyte, Seattle Genetics, and Ono; shareholder/co-founder of Jounce Therapeutics; holds a licensing arrangement with Evelo; an inventor on patent 15/170,284 submitted by the University of Chicago that covers the use of microbiota to improve cancer immunotherapy. 

Science. Published January 5, 2018.  Jobin abstract, Gajeski et al abstract, Wargo et al abstract, Routy et al abstract

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