The composition of patients' gut microbiomes influences whether they will respond to anti–PD-1 therapy, according to a trio of recently published studies. One of the studies also found that using antibiotics can reduce treatment efficacy, presumably by killing important species of gut bacteria. Now researchers are investigating how these findings can be used to increase the proportion of patients who respond to checkpoint inhibitor therapy.
The composition of a patient's gut microbiome can determine the likelihood of response to checkpoint inhibitor therapy, according to a trio of studies published in Science.
“It is very exciting that three groups around the world, working independently, found the same thing,” says Bertrand Routy, PhD, of Gustave Roussy in Paris, France, lead author of one of the papers (Science 2018;359:91–7).
Routy's study prospectively analyzed the fecal microbiomes of 153 patients with non–small cell lung cancer (NSCLC) or renal cell carcinoma (RCC). The two other studies each analyzed fecal microbiome data for more than 40 patients with melanoma. All three teams showed that the type of gut bacteria present before anti–PD-1 therapy began was consistently different between patients who responded and patients who did not. Furthermore, when mice received fecal transplants from responding patients and were then injected with cancer cells, they exhibited better responses to anti–PD-1 therapy than mice that received transplants from nonresponding patients.
Routy's study also found that 69 patients with NSCLC, RCC, or urothelial carcinoma who received antibiotics within the 2 months before or 1 month after beginning anti–PD-1 therapy were more likely to develop resistance.
“Together, these studies have important implications for the role of the gut microbiome in cancer therapy, including the notion that perhaps we can enhance responses by modulating the gut microbiome,” says Jennifer Wargo, MD, of The University of Texas MD Anderson Cancer Center in Houston, senior author of the first melanoma article (Science 2018;359:97–103).
Scientists are eager to identify the factors that influence which patients benefit from checkpoint inhibitors. On the basis of prior work in mice and correlative studies in humans, “we thought maybe the gut microbiome would be a minor modulating factor,” explains Thomas Gajewski, MD, PhD, of the University of Chicago in Illinois, senior author of the second melanoma study (Science 2018;359:104–8). “But right now—at least in our cohort of patients—it seems to be a major factor impacting clinical efficacy.”
The magnitude of the change in anti–PD-1 response associated with antibiotic use in Routy's study, presumably due to the disappearance of important bacterial species in the gut, was also striking. “One important takeaway is that antibiotic treatment near the time of anti–PD-1 therapy decreases efficacy, and that avoiding the use of antibiotics as much as clinically feasible may double the proportion of cancer patients responding to therapy,” says Giorgio Trinchieri, MD, director of the Cancer and Inflammation Program at the NIH, who was not involved in these studies.
However, Routy cautions that his group's findings shouldn't scare away patients from taking antibiotics needed to treat bacterial infections. “Antibiotics save lives,” he emphasizes.
In addition to demonstrating the importance of the gut microbiome in checkpoint inhibitor therapy, these studies raise many questions. First, which are the most important bacteria for promoting patient response to checkpoint inhibitors? Although the three studies found that, across cancers, some types of bacteria were consistently enriched in individuals who responded to checkpoint inhibitors, the species of bacteria with the strongest links to response were different in each study: Akkermansia muciniphila and Enterococcus hirae in NSCLC and RCC; Faecalibacterium in the first melanoma study; and Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium in the second melanoma study. Wargo says that these differences could be due to geographic or dietary differences among the cohorts.
Gajewski predicts that a handful of bacteria with immune-stimulating effects will eventually be identified. “The mechanism of each one might be slightly different. There might be several ways to boost an immune response from different angles.”
Indeed, the question of mechanism remains open. The primary tumors in these studies were located outside of the colon. “How do bacteria in the gut change immune cells in the tumor, which is in a different place?” asks Gajewski.
All three labs plan to delve into the molecular mechanisms underlying their results. For example, Routy says that his lab is now investigating the role that CD4+ cells expressing the chemokine receptors CCR9 and CXCR3 play in linking the gut microbiome to immunotherapy response.
Another question raised by the findings is whether the composition of the gut microbiome could provide a useful biomarker of checkpoint inhibitor response, says Wargo.
“If you knew that a patient was unlikely to respond to just anti–PD-1 treatment, you might step up the therapy by giving combination therapy,” Gajewski offers as an example.
Currently, Wargo's lab is working with the Parker Institute for Cancer Immunotherapy at MD Anderson to initiate a clinical trial testing whether modulating the gut microbiome—via fecal transplant, for example—can increase the percentage of patients whose tumors shrink in response to checkpoint inhibitors. Meanwhile, Gajewski's lab is teaming up with Evelo Biosciences in Cambridge, MA, to test whether a probiotic containing Bifidobacterium can expand the number of patients who respond to checkpoint inhibitors. Both trials are expected to start this year.
“We need much better information to understand what a ‘good’ microbiome is—that is, which species increase therapy efficiency while limiting toxicity,” says Trinchieri. “These papers are an important step forward to increasing this understanding.” –Kristin Harper