Fecal Transplant Overcomes Nivolumab Resistance in Melanoma

M. Alexander Otto, PS, MMS

December 17, 2020

In a small clinical trial, fecal transplants restored the response to immunotherapy in 3 of 10 patients with refractory metastatic melanoma whose conditions had stopped responding to treatment with anti–programmed cell death–ligand-1 (anti-PD-LI) drugs.

One of these patients had a complete response to nivolumab, assessed by tumor regression on PET-CT scan, and the other two had partial responses. All three were progression free at 6 months.

"We were surprised by the clinical results. We expected an immune change and some clinical effects, but not a complete response," lead author Erez Baruch, MD, PhD, told Medscape Medical News.

Baruch is now at the University of Texas Health Science Center, Houston, Texas. He was previously at the Sheba Medical Center and Tel Aviv University, Tel Aviv, Israel, where the study was conducted.

The fecal transplants came from two other patients with metastatic melanoma who had experienced complete responses to checkpoint inhibition that lasted at least a year.

The three patients whose conditions responded, as well as two additional patients, underwent transplant from the same donor.

Five patients who underwent transplant from a second donor did not have a response, for unclear reasons, the researchers comment. There was no obvious association between microbiome composition after transplant and clinical response.

However, the study wasn't powered to assess efficacy between the two donors, only safety. The only safety signal was temporary mild bloating, which occurred in one patient, they note.

The results were published recently in Science.

Although the trial was small and had no control group, the study supports an emerging concept in oncology that the gut microbiome, already known to have a powerful effect on the immune system, might also influence response to immunotherapy and enhance its effect, the investigators comment.

"The key finding is that microbiota modulation in cancer is clinically meaningful. Changing the gut microbiota composition and reinducing immunotherapy may, in some patients, lead to clear clinical responses," they add.

Baruch cautioned against "a sudden massive use of probiotics or do-it-yourself" fecal transplants, noting that "this is only the first step in microbiota modulation in cancer patients, and we definitely don't know enough" to move beyond clinical trials.

The investigation is ongoing. The recruitment target is 40 patients. The team plans to expand the study to include additional malignancies, among them, non–small cell lung cancer.

Gut Microbiome "Wiped Out"

All 10 participants in this trial underwent a 3-day course of vancomycin and neomycin, the aim of which was to wipe out the patients' own gut microbiome. They then received a fecal transplant administered both by colonoscopy and oral capsules.

Immunotherapy was then reintroduced (standard-dose IV nivolumab). Patients continued to take oral stool capsules in cycles that were repeated every 2 weeks for six cycles.

Reinduction of immunotherapy occurred after a median of 113 days. Among patients who experienced a clinical response, the median was 119 days. That time frame is too short for reemergence of tumor cells that are susceptible to immunotherapy, which is a potential confounder, the researchers comment. It was also unlikely that the responses that occurred were delayed responses to previous anti–programmed cell death protein–1 (anti-PD-1) treatment, another potential confounder.

The recipients varied widely with respect to the composition of gut microbiota before transplant; after transplant, the microbiota took on the characteristics of their donors' microbiota.

The microbiota of both donors had an abundance of the immunotherapy-favorable Lachnospiraceae, but abundance of Veillonellaceae, also favorable for immunotherapy, was higher in the first donor's. The transplant from that donor led to the three responses.

For recipients from the first donor, immune-related gene sets on gut and tumor biopsy specimens were upregulated. This did not occur for patients who received transplants from the second donor. For recipients from the first donor, there was also an increase in gut infiltration and in activity of antigen- presenting cells.

In the participant who had a complete response, there was no pretransfer tumor PD-LI expression. For the two patients who experienced partial responses, tumor PD-LI expression was ≥5%.

"Clinical institutions should not be deterred by the lack of sufficient mechanistic knowledge to examine the clinical potential of [fecal transplant] in the setting of well-designed and supervised human trials. This is especially true for refractory patients, in whom the risk-benefit ratio" is favorable, the investigators say.

The study received no funding from industry. Baruch has disclosed no relevant financial relationships. Other investigators have numerous relationships with pharmaceutical companies, including Bristol-Myers Squibb, the maker of nivolumab. One holds a patent on enhancing checkpoint blockade by manipulating the microbiome.

Science. Published online December 10, 2020. Abstract

M. Alexander Otto is a physician assistant and award-winning medical journalist who has previously worked for several major news outlets, including McClatchy and Bloomberg BNA. He is a former MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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