Backup from bacteria?
HOUSTON—Research into the gut microbiome—the millions of bacteria that live in the human digestive tract—and how it impacts health has become a topic of growing interest as scientists identify new ways these bacteria affect immunity and disease pathogenesis and maintenance. And the latest of those diseases that are impacted by the microbiome is now being shown to include cancer. A team led by The University of Texas MD Anderson Cancer Center researchers recently shared results in Science detailing how the gut microbiome can impact response to immunotherapy.
“You can change your microbiome, it’s really not that difficult, so we think these findings open up huge new opportunities,” said study leader Dr. Jennifer Wargo, associate professor of Surgical Oncology and Genomic Medicine. “Our studies in patients and subsequent mouse research really drive home that our gut microbiomes modulate both systemic and anti-tumor immunity.”
Gut microbiomes can be altered through diet, exercise, antibiotics, probiotics or fecal transplants, according to Dr. Vancheswaran Gopalakrishnan, lead co-first author. The latter type of procedure has had success in treating patients with C. diff. infection, and is being explored in gastrointestinal disorders such as Crohn's disease, ulcerative colitis and inflammatory bowel disease. If the proper bacteria can be isolated and transplanted, this research suggests that it could potentially be an option for targeting cancer as well.
Wargo and colleagues took buccal swabs (from the inside of the cheek) and fecal samples from metastatic melanoma patients treated with anti-PD-1 therapy, which blocks the PD1 protein on T cells, acting as a brake on the immune system. The patients included 30 individuals who responded to anti-PD-1 treatment and 13 who did not respond. The samples were then run through 16S rRNA and whole-genome sequencing. No significant differences in response or progression were seen among the buccal samples, but the fecal samples yielded more helpful results. They found that the patients with more diverse gut bacteria saw longer median progression-free survival (PFS), which they defined at the time point where 50 percent of the studied patients saw disease progression. Though the high diversity group did not reach median PFS, those with low or intermediate diversity saw median PFS of 188 and 232 days, respectively.
The sequencing also revealed that patients who responded to anti-PD-1 therapy presented with microbiomes in which the Ruminococcaceae family of bacteria was enriched, while non-responders had microbiomes enriched in the Bacteroidales order. Those with an abundance of the genus Faecalibacterium (of the Ruminococcaceae family and Clostridiales order) saw much longer PFS, with the median not reached, while the patients lacking in that bacteria type had a median PFS of 242 days. An abundance of Bacteroidales was also linked to more rapid disease progression. Study participants with high levels of Clostridiales/Ruminococcaceae also presented with higher levels of circulating T cells that kill abnormal cells and greater T cell penetration into tumors. Those with higher levels of the 'bad' bacteria had higher levels of circulating regulatory T cells, as well as myeloid-derived suppressor cells and a dampened cytokine response, which suppresses anti-tumor immunity.
When Wargo and her colleagues tested their results by transplanting fecal microbiomes from responding patients to non-responders (by performing fecal microbiome transplants into germ-free mice), the receivers saw significantly reduced tumor growth, better outcomes after immune checkpoint blockade treatment, high prevalence of beneficial T cells and lower levels of immune-suppressive cells.
Co-first authors of the paper for this work, titled “Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients,” are Christine Spencer and Dr. Luigi Nezi, both of the department of Genomic Medicine at MD Anderson.
At present, the team is working together with the Parker Institute for Cancer Immunotherapy on designing a clinical trial that will evaluate the combination of checkpoint blockade with microbiome modulation.
The Parker Institute announced on Nov. 14 that it had begun a collaboration with MD Anderson and Seres Therapeutics Inc. to explore the potential of Seres' microbiome therapies to improve outcomes for cancer patients currently being treated with immunotherapies. Seres gained an exclusive option to license intellectual property rights from MD Anderson related to combining bacteria with checkpoint inhibitors. The trial will be a randomized, placebo-controlled clinical study in patients with advanced metastatic melanoma at MD Anderson, sponsored by the Parker Institute. The focus will be determining what affect, if any, combining an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy will have on patients outcomes. The therapy in question, SER-401, is a preclinical-stage oral microbiome therapy that consists of “a rationally designed consortium of live bacteria.”
“MD Anderson, and in particular Dr. Wargo’s laboratory, is leading the charge to better understand the microbiome and the response to immune checkpoint inhibitors,” Dr. Roger J. Pomerantz, president, CEO and chairman of Seres, said in a press release announcing the collaboration. “We look forward to combining our insights and capabilities with both MD Anderson and the Parker Institute to advance microbiome therapies to augment Immunotherapy in cancer patients toward the clinic, with the ultimate goal of improving outcomes for patients facing life-threatening tumors with significant unmet medical need.”