But how bacteria improve the immune response is not yet clear. Patients carrying favorable bacteria in their gut had higher CD-8 T cell counts and more antigen-presenting cells, Dr Wargo says, suggesting one way the “right” bugs may prime the immune system to better recognize cancer cells. Seres hopes to capture enough of those beneficial bugs in its pill formulation to boost patient responses to anti-PD1 therapy, now estimated at only about 25 percent.5
Although the idea of using bugs as drugs is still its infancy, scientists say the earliest uses in gastrointestinal conditions, especially against the bacterium Clostridium difficile, have enjoyed some success. When these antibiotic-resistant gut infections occur, replenishing normal bacteria through fecal microbiota transplant works beautifully, according to Giorgio Trinchieri, MD, head of the cancer immunology section and a distinguished investigator at the National Cancer Institute in Bethesda, Maryland. Most patients who develop these infections are usually older and sick, he says, so “in this case, we give them back bacteria we all have.”
But, in cancer, it’s more difficult,” Dr Trinchieri says. “You need to know exactly what a ‘good’ microbe is and we’re not there yet.”
As to the latest cancer research, including Dr Wargo’s findings and a study out of France suggesting that antibiotics may undermine the effectiveness of checkpoint inhibitors, Dr Trincheri describes it as important work.6 “Most studies before now have all been done in the mouse,” he says. “These clearly show a clinical relevance.”
In addition to the impending Texas trial, a second clinical study at the University of Pittsburgh Schools of Health Sciences is poised to begin soon. Investigators there will use fecal transplants to treat patients with advanced melanoma who fail anti-PD-1 immunotherapy.7 Normal bacteria from patients with melanoma responding to these drugs will be delivered through colonoscopy into the guts of non-responders.
Diwakar Davar, MD, the lead investigator and an oncologist/hematologist in the university’s Hillman Cancer Center, says the Pittsburgh study is the first to gain US Food and Drug Administration (FDA) approval specifically to treat cancer. Recruitment is already under way, he says, and the first transplant is expected to take place in February 2018.
Stools from both donors and recipients will be characterized for the presence of bacteria, viruses, and other microbes before transplantation. Only donors who are 2 years or more out from their anti-PD-1 therapy will be accepted, Dr Davar says, as those responding for this length of time carry the lowest risk of relapse — and presumably the best cancer-fighting microbes.
Ultimately, as results of these and other early studies unfold, scientists hope to define what constitutes a functionally healthy microbiome not just in cancer, but across the health spectrum. Doing so raises the prospect that monitoring or manipulating these lifelong passengers inside us can, someday, improve human health.
“It all goes back to the ecology of the gut,” where most microbes live, said Dr Trinchieri. “Once developed, our microbiota stay pretty constant throughout our lives,” he says — that is, until aging or disease transforms them into potential pathogens.
- NIH HMP Working Group, Peterson J, Garges S, et al. The NIH human microbiome project. Genome Res. 2009;19(12):2317-23. doi: 10.1101/gr.096651.109
- Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012;70(suppl 1):S38–S44. doi: 10.1111/j.1753-4887.2012.00493.x
- Seres Therapeutics, MD Anderson Cancer Center, and the Parker Institute for Cancer Immunotherapy announce a collaboration to support the investigation of microbiome therapeutics for immuno-oncology [news release.] Houston, TX: The University of Texas MD Anderson Cancer Center; November 14, 2017. https://www.mdanderson.org/newsroom/2017/11/seres-therapeutics-md-anderson-cancer-center-parker-institute-announce-collaboration.html. Accessed December 2017.
- Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2017 Nov 2. doi: 10.1126/science.aan4236 [Epub ahead of print]
- NCI Staff. Checking in on cancer checkpoint inhibitors. National Cancer Institute website. https://www.cancer.gov/news-events/cancer-currents-blog/2015/gulley-checkpoint. Published December 18, 2015. Accessed December 2017.
- Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2017 Nov 2. doi: 10.1126/science.aan3706 [Epub ahead of print]
- ClinicalTrials.gov. Fecal microbiota transplant (FMT) in melanoma patients. NCT03341143. https://clinicaltrials.gov/ct2/show/NCT03341143. Accessed December 2017.