Fecal Microbiota Transplants May Improve Resistance to Melanoma Immunotherapy

Doug Brunk

October 21, 2021

In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their phase 1 clinical trial designed to determine if fecal microbiota transplantation (FMT) could reprogram the gut microbiome in advanced melanoma patients who failed to respond to anti–programmed death 1immunotherapy.

Dr Hassane Zarour

Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers' sense of anticipation was palpable. "It's a high-risk, high-reward study, so you never know," Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center's Hillman Cancer Center, said in an interview.

For the study, which was funded by the National Institutes of Health and published in Science, Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.

After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.

"This opens new doors for the future," Zarour said. "It's very encouraging, but I don't want to overstate the data. It's a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn't think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great."

Dr Teri Greiling

Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome's potential to influence the course of melanoma and other diseases. "What's emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota," said Greiling, associate professor of dermatology at Oregon Health & Science University, Portland.

"From day 1 of birth, we're colonized by microbes that train our immune system how to function," Greiling said. "In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally."

Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. "We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we're up over 50%, which is amazing in a decade," Greiling said. "Still, we're losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it's hard to extrapolate from such small numbers."

Positive Results in an Israeli Study

Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.

Dr Erez Baruch

"We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders," the study's lead author, Erez N. Baruch, MD, PhD, told this news organization. "Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy."

Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new "playing ground" for drug development that can support existing immunotherapies. "It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients," he said. "Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there's an indication."

As for next steps, Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants "to better determine what the good and bad bugs are," he said. "There are so many variables, including diet and geography. We need more data." The hope is to develop a "microbiome signature" to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.

"We don't want to say that the microbiome is responsible for everything, but it's responsible for some of the response and some of the resistance to treatment," Zarour said. "So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that."

Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. "These usually can be done in the setting of large cancer centers and will probably not be available in any hospital," he said. "This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs."

Dr Tamia Harris-Tryon

Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. "We know that the diet impacts the repertoire of microbes that colonize the gut," said Harris-Tryon, assistant professor in the department of dermatology at the medical center. "The diet of the recipient likely has an impact" on the success of donor FMT.

She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. "Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered," she said.

According to Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. "That is very important, especially with combination therapy," he said. "There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes."

Studies Raise More Questions

In the opinion of Greiling, results from these two studies raise more questions than they answer. "The big question...is why and how does FMT work, and how can we make the response better?" she said. "Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it's a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?"

Then there are pending regulatory concerns. "We know that FMT works for [Clostridioidesdifficile colitis but it's not officially [Food and Drug Administration] approved," Greiling said. "The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes."

The UPMC clinical trial was supported by Merck. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Greiling and Harris-Tryon reported having no relevant financial disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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