Gut Microbiome Assemblage Impacts Response to Cancer Immunotherapy

University of Chicago Medicine researchers report that specific microbiome assemblages can boost the response rate to immunotherapy for patients being treated for advanced melanoma. Their study (”The Commensal Microbiome Is Associated with Anti–PD-1 Efficacy in Metastatic Melanoma Patients”) is published in Science.

“Anti–PD-1–based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients’ microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response,” write the investigators.

“Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti–PD-L1 therapy. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.”

B. longum, C. aerofaciens, and E. faecium were much more prevalent in the intestines of 16 patients who responded to treatment (38%) than in the 26 patients (62%) who did not. The presence of these specific bacteria in the intestine appears to enhance T-cell infiltration into the tumor microenvironment and augment T-cell killing of cancer cells, increasing the odds of a vigorous and durable response.

The strong correlation between specific gut bacteria and a clinical response to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy suggests “a causal relationship,” said study director Thomas Gajewski, M.D., Ph.D., the AbbVie Foundation Professor of Cancer Immunotherapy at the University. “Specific bacteria clearly contribute to improved antitumor immunity in patients. The gut microbiota has a more profound effect than we previously imagined.”

The current study follows a November 2015 Science paper from Dr. Gajewski’s laboratory, one of the first to connect the presence of specific intestinal bacteria to greater potency for immunotherapy. These initial papers showed that the composition of the gut microbiome can influence how well these cancer immunotherapies work in mice.

Although the earlier mouse data was striking, “we knew there were multiple barriers that can decrease the odds that immunotherapy will work,” Dr. Gajewski said. “We initially thought the microbiome was a minor component. But in our current study, these bacteria were a very strong predictor of who would respond.”

The current paper focuses on 42 human patients going through treatment for metastatic melanoma. The researchers collected stool samples from each patient prior to treatment. Thirty-eight patients then received an anti-PD-1 drug, so-called checkpoint inhibitors such as nivolumab or pembrolizumab. Four more patients received a related drug, anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA4) (ipilimumab). The researchers focused on eight bacterial species that were more prevalent in patients who did respond to therapy as well as two species that were more abundant in patients who did not respond. Because of bacterial variations, the team used three different methods to determine the genetic sequences of the microbes.

Patients with a higher ratio of the “beneficial” bacteria to “nonbeneficial” bacteria all showed a clinical response, meaning a reduction in tumor size. The scientists then ran a smaller experiment in reverse. They collected fecal bacteria from three human subjects who responded favorably to treatment and three who did not respond. They transferred those bacteria into the intestines of germ-free mice. Two weeks later they implanted melanoma cells in the mice.

Two out of three mouse groups given bacteria from human responders had slow-growing tumors and two out of three with fecal material from human nonresponders had fast-growing tumors. Mice treated with PD-1–blocking drugs only showed tumor shrinkage if they had microbiota from responding patients.

“Our results strongly suggest that the microbiota is a major factor, a gatekeeper for the immune response against a tumor,” Dr. Gajewski said. “Without microbial support, the immune response just never quite gets going. Our results have pushed us in two directions. We have to start experimenting with probiotics as a way to enhance immunotherapy. We hope to launch a clinical trial using Bifidobacteria in 2018.”