Model of gut microbiome
Scientists at the Pacific Northwest National Laboratory are developing a model of the microbial environment inside the human gut. This model, which is composed of three- dimensional human intestinal cells cultured with specific gut bacteria, provides an approach to study how changes in bacteria affect gut health and overall human health. For example, the model can help researchers understand how changes in certain bacterial populations within the gut may be connected to colon cancer and other diseases.

The microbiome has been implicated in many areas of human health, and cancer is no exception. Over the past few years, evidence has emerged that consistently indicates that the microbiome in the gut as well as in the tumor may affect whether patients with cancer respond to immunotherapy.

Retrospective analyses have shown repeatedly that a type of immunotherapy called checkpoint inhibition may be less effective in patients with advanced cancer who receive antibiotics—which can effectively wipe out the gut microbiome—and checkpoint drugs at about the same time. For example, in metastatic non-small-cell lung cancer, patients who received antibiotics within 6 weeks of immune checkpoint inhibitor treatment lived a median of only 4 months while patients who did not receive an antibiotic lived 12.6 months, a difference that was statistically significant (P = .005).1 This association has also been shown for metastatic renal cell carcinoma and metastatic melanoma, two other cancer types for which immune checkpoint inhibitors are increasingly indicated.2,3

George Miller, MD, principal investigator and director of the S. Arthur Localio Laboratory in the Department of Surgery at NYU School of Medicine, tells GEN that this emerging linkage is “not surprising” because the microbiome has “a lot of control over” the immune system.

Illuminating obscure connections

To substantiate the association between antibiotic use and immunotherapy response, researchers have started teasing out the underlying mechanistic details. Besides cementing the observed association, such details could lead to the development of therapeutic strategies that modulate the microbiome to boost immunotherapy response.

Several studies have found unique populations of bacteria to be associated with immunotherapy response. For instance, in a study that evaluated the efficacy of immunotherapy in metastatic melanoma patients, stool samples taken before patients received anti-PD-1, a checkpoint inhibitor, revealed that certain bacterial species—Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium—were more common among patients who ultimately responded to therapy.4

The relationship between the gut microbiome and the tumor microbiome is another area of active research, and evidence suggests that such a relationship exists. For example, in a study of the cancer pancreatic cancer microbiome, immune suppression was shown to be largely driven by macrophages, specifically M2 type macrophages. In fact, expansion of these immune cells was found to be promoted by gut bacteria that accessed the pancreas. When the microbiome was ablated, there were fewer immunosuppressive macrophages and a better T-cell response to the tumor. Altogether, these results suggest a relationship between the gut and tumor microbiome.5

Building upon these findings, a different research group compared the tumor microbiome from short-term and long-term survivors of pancreatic cancer and found that long-term survivors had higher diversity in the tumor microbiome and a unique microbial signature that predicted long-term survivorship. When mice were transplanted with fecal material from patients, the tumor microbiome and tumor growth was affected, providing evidence of crosstalk between the gut and tumor microbiome.6

Confronting baffling inconsistencies

Although evidence from across cancer types is accumulating and revealing links between the microbiome and immunotherapy, it has yet to establish anything like a microbiome–immunotherapy field. Progress has been slowed, in part, by seeming contradictions that have yet to be explained.

For example, the general observation that antibiotic use can compromise immunotherapy seems to clash with the specific findings from the study of the pancreatic cancer microbiome. In this study, mice with pancreatic ductal adenocarcinoma were subjected to microbiome ablation with broad-spectrum antibiotics, an intervention that improved the response to immunotherapy. In this case, the mice received the immune checkpoint inhibitor anti-PD-1.5 A similar observation was made in a study in which a mouse model was used to show that microbiome ablation could improve the response to gemcitabine, a common chemotherapeutic used to treat ovarian, breast, lung, and pancreatic cancers.7

When asked why the effect of antibiotics on the response to immunotherapy appears to vary, Rob Knight, PhD, the faculty director of the Center for Microbiome Innovation at the University of California, San Diego, tells GEN that “very few” cohort studies of a given cancer type have been done across more than one center. As a result, in general, it’s “difficult” to tell whether the response to immunotherapy is due to the cancer type or study center. “What we’re going to need,” he insists, “is a lot more studies that are multicenter and look at different groups of people with the same tumor.”

The seeming inconsistency between the findings for pancreatic cancer and the findings for other cancers could have another explanation, suggests Florencia McAllister, MD, assistant professor in the Department of Clinical Cancer Prevention at the University of Texas MD Anderson Cancer Center. She points out to GEN that the findings for pancreatic cancer come from animal studies, whereas the findings for other cancer types come from human studies.

In patients with pancreatic cancer, immune checkpoint inhibitors have largely failed to show clinical activity. Consequently, for this particular cancer type, it has been difficult to study the relationship between antibiotic use in humans and their immunotherapy response.8

“All of this has just happened in the last two years,” stresses Knight. “We’re at a point where there’s a lot of promise but not a lot of solid clinical evidence.”

Turning bugs into drugs

Although exactly how the microbiome influences the immunotherapy response remains unclear, the field is pushing forward with clinical trials that are evaluating several strategies that aim to enhance therapeutic efficacy by modulating the microbiome. Such strategies include fecal microbial transplantation, prebiotics, probiotics, and dietary modifications. Even bacteriophage approaches are being considered. In these approaches, a virus would attack specific bacteria believed to be dampening immunotherapy response. “There are certainly broad-based efforts in the community to try out different strategies modulating the microbiome in the context of immunotherapy,” says Knight.

In particular, clinical trials are currently evaluating whether a consortium of bacteria packaged in pill form could boost the immunotherapy response. A clinical trial launched by the Parker Institute for Cancer Immunotherapy in 2019 is evaluating whether combining investigational microbial product SER-401 with immune checkpoint inhibitor nivolumab improves efficacy in patients with melanoma.9 A different clinical trial, one sponsored by Evelo Biosciences, is assessing whether combining investigational microbial product EDP1503 with immune checkpoint inhibitor pembrolizumab influences treatment efficacy. The combination is being evaluated in several cancer types, including triple-negative breast cancer, colorectal cancer, and non-small-cell lung cancer.10

Early data from clinical trials that evaluated fecal microbial transplantation as a microbiome modulation strategy are being reported. Two clinical trials, one conducted at the University of Pittsburgh and the other at Sheba Medical Center in Israel, enrolled melanoma patients who did not respond to immune checkpoint blockade and treated them with fecal transplantation. In these trials, fecal matter was donated by patients who achieved a complete response to immunotherapy.11,12

Updated data from each trial were presented at the Microbiome, Viruses, and Cancer conference hosted by the American Association for Cancer Research (AACR) earlier this year. This data showed about a 30% response rate in the U.S. trial, which evaluated patients with melanoma who previously did not respond to immune checkpoint blockade. A similar response rate was observed in the Israel trial. “We’re seeing evidence that this can actually work,” Jennifer Wargo, MD, associate professor of Surgical Oncology and Genomic Medicine at University of Texas MD Anderson Cancer Center, tells GEN.

However, Wargo adds, “We don’t know the best way to modulate the microbiome yet.” She explains that fecal transplantation is likely the necessary first step, but that there are “a lot” of unknowns as to the best way to do this. For instance, it’s unclear who the ideal donors are. She asks, “Are compete responders to immunotherapy the perfect donor, or should we be using healthy donors?”

gut microbiome impacts the response to anti- PD-1 immunotherapy in melanoma patients
A study led by MD Anderson scientists demonstrated that the gut microbiome impacts the response to anti- PD-1 immunotherapy in melanoma patients. The scientists performed fecal microbiome transplant (FMT) studies from responding patients on PD-1 blockade (R) or from nonresponding patients (NR). In these studies, mice receiving FMT from R had enhanced systemic and antitumor immunity, with more immune cells in the tumor and in the gut of the transplanted animals. Conversely, mice receiving FMT from NR had poor antitumor immunity and a paucity of immune cells in the gut.

Also, the safety of fecal transplantation has been called into question. Last year, an article appeared in the New England Journal of Medicine describing two patients who were treated with fecal transplantation for noncancer indications. Both patients developed multidrug-resistant infections, and one of the patients died.13

Although the microbiome appears to play a role in the immunotherapy response, elucidating this role doesn’t mean a straightforward means of boosting the response rate, which is around 12% for immune checkpoint inhibitors, will emerge.14 Any improvements may need to come from efforts that account for multiple factors. Besides the microbiome, factors contributing to the immunotherapy response include tumor mutational burden, biomarker expression, tumor microenvironment, and genetics.

“When you think about how complex cancer is, why it develops, grows, and metastasizes, and why it does or doesn’t respond to treatment, [it] is really from a multitude of different reasons,” Wargo says. “It takes an orchestra, not a soloist, to cure cancer.”



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