Changes in an individual’s gut microbiome, which comprises more than a trillion bacteria and other microbes, can occur with various diseases, including cancer. While the relationship between the gut microbiome and cancer remains largely unknown, researchers have found an association between the microbiome and response to immunotherapy in patients with metastatic melanoma.
In the past few years, researchers have learned much about the gut microbiome and its role in maintaining health. So far, investigators in the United States, China, and Europe have sequenced the collective microbial genomes of hundreds of individuals and catalogued several million genes.
More recently, preclinical research has indicated a link between the microbiome and the response to immune checkpoint inhibitors in mice with melanoma. To see whether this finding could be replicated in humans, researchers led by Jennifer Wargo, M.D., M.M.Sc., an associate professor in the Departments of Surgical Oncology and Genomic Medicine and co-leader of the Melanoma Moon Shot Program at The University of Texas MD Anderson Cancer Center, investigated the relationship between gut bacterial genetic signatures and the response to immune checkpoint inhibitors in a series of patients with metastatic melanoma.
“Our findings have important implications and suggest that perhaps we should be profiling the gut microbiome of patients before treatment with immune checkpoint inhibitors,” Dr. Wargo said. “Furthermore, our data suggest that we may be able to modulate the gut microbiome to enhance responses to immune checkpoint inhibitors.”
Searching for biomarkers
Dr. Wargo and her team have worked to identify biomarkers of response to drugs that inhibit the immune checkpoint protein PD-1 (programmed cell death protein 1). “Anti–PD-1 therapy is effective for many, but not all, patients with metastatic melanoma,” Dr. Wargo said. “And in some patients, the responses aren’t durable. We want to find ways to enhance response rates as well as the durability of responses.”
As part of a larger study, the researchers obtained oral and fecal samples from metastatic melanoma patients before treatment with PD-1 inhibitors. 16S rRNA gene sequencing, a standard technique for identifying bacterial taxa, was used to characterize each patient’s gut microbiota.
Using Response Evaluation Criteria in Solid Tumors, Dr. Wargo and her colleagues evaluated the patients’ responses to PD-1 inhibition and divided the patients into two groups—responders and nonresponders—for analysis. “Our hope going into the study was to identify particular gut bacterial signatures that correlate with response to therapy,” said Vancheswaran Gopalakrishnan, B.D.S., M.P.H., a graduate research assistant in Dr. Wargo’s laboratory and a Ph.D. candidate.
Results of an early analysis of 30 responders and 13 nonresponders to PD-1 inhibition were presented at the 2017 American Society of Clinical Oncology–Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium. While no differences were seen in the oral microbiome, responders to PD-1 inhibition had a higher overall bacterial diversity and a larger proportion of bacteria belonging to the Ruminococcaceae family in the gut microbiome at baseline compared with nonresponders. In contrast, the gut microbiome of nonresponders was enriched in bacteria belonging to the Bacteroidales order.
“Based on these findings, we feel that distinct signatures exist in the gut microbiomes of responders versus nonresponders to immune checkpoint inhibitors,” Mr. Gopalakrishnan said. “And these signatures may dictate response to the treatment.”
“Our findings indicate two areas for additional research: further characterizing the diversity and composition of the gut microbiome to predict response to immunotherapy and modulating the gut microbiome to enhance treatment,” Dr. Wargo said.
Dr. Wargo, Mr. Gopalakrishnan, and their colleagues are already using multiple technologies to elucidate the mechanisms that might be involved in treatment response. For example, whole genome shotgun sequencing may reveal additional differences—including differences in functional capacity—between the gut microbiomes of responders and nonresponders in the current study.
Even as they strive to learn more about the gut microbiome’s effect on treatment response, the researchers are planning a clinical trial in which the gut microbiomes of patients with metastatic melanoma will be altered to create a more favorable gut microbiome. The researchers hypothesize that this favorable bacterial genetic signature will maximize the patients’ chances of a response to PD-1 inhibition.
For more information, contact Dr. Jennifer Wargo at 713-745-1553 or email@example.com.
OncoLog, July 2017, Volume 62, Issue 7