In patients with advanced melanoma whose disease progressed on immunotherapy, the use of fecal microbiota transplant achieved objective responses, in a phase I study.
In a phase 1 trial of patients with advanced melanoma whose disease progressed on immunotherapy, objective responses were achieved with the use of fecal microbiota transplant (FMT) in 30% of those who were re-challenged with a PD-1 inhibitor (NCT03353402).
“Over the past few years…[leading research has] indicated that there is a strong association between the composition of the microbiome and successful immunotherapy,” Gal Markel, MD, PhD, said during his presentation that was made available as part of the virtually held National Institutes of Health–American Association of Cancer Research Cancer, Autoimmunity, and Immunology Conference. “We hypothesized that if the relationship between the microbiome and immune system is a cause-and-effect [association], then alteration of the microbiome should, or could, lead to an immune response and a clinical response.”
Patients receiving FMT were those with metastatic melanoma who had progressed on at least 1 line of PD-1 inhibitor therapy, confirmed progression on previous immunotherapy by imaging and histology, healthy colonic mucosa, and no contraindications to colonoscopy. In addition, patients with BRAF V600 mutations who were eligible for BRAF/MEK inhibitors must have failed targeted therapy. Patients were to be treated with FMT and reintroduction of a PD-1 inhibitor.
Because it is unknown which bacteria or consortia are the main drivers of the immune system of patients with advanced cancer, the investigators relied on certain clinical characteristics of donors with metastatic melanoma rather than healthy donors. These characteristics included patients who had an ongoing durable complete response to PD-1 inhibitor therapy, were still on active treatment, and were approved for feces donation according to current standard guidelines.
“If indeed this relationship is cause and effect, then [we thought it possible to] transfer the whole microbiome of patients who achieved durable and complete response on anti–PD-1 [inhibitor therapy] into recipients who have progressed on all lines of therapy,” said Markel.
Patients underwent depletion of native microbiota with antibiotics and polyethylene glycol-based diarrhea solution for 3 days. Colonoscopy was performed with induction FMT followed by orally ingested capsulized FMT. Repeated cycles of maintenance capsulized FMT and PD-1 inhibitor therapy occurred every 14 days for a total of 6 cycles, with immune checkpoint inhibitor monotherapy continuing starting at day 100 (FIGURE).
PET/CT imaging was performed at baseline, day 65, and then every 9 to 10 weeks thereafter. Sigmoidoscopy and gut biopsy were performed on day 31; tumor biopsy was performed at baseline and again between days 62 and 70. Pre- and posttherapy tumor samples were collected.
The primary end points of the study were microbiome alteration and safety as measured by FMT- and immune-related adverse effects (AEs) as well as serious AEs. Secondary and exploratory end points included alteration of the immune system activity as measured by post-FMT gut CD68-positive and intratumoral CD8-positive cells, and objective therapy response by immune-related iRECIST (irRECIST) criteria.
Two donors were identified and 10 comprised the recipient group, all of whom were heavily pretreated. Eight patients had visceral or central nervous system metastases with high lactate dehydrogenase levels or high disease burden. There were no grade 2 or greater AEs of any kind, such as perforation and septic shock, and all patients were fully recovered 3 to 4 hours after the colonoscopy. None of the patients on the trial experienced any immune-related AEs.
Alterations in the microbiome were monitored by a deep-sequencing approach in each donor group, which was composed of half of the overall cohort each. After receiving FMT, patients were able to be identified by donor groups indicating that the investigators were successful in altering the recipients’ microbiome.
Biopsies for determining immune system activation were evaluated by immunohistochemistry. Nine of 10 patients had increased CD68 staining expression in posttreatment biopsies versus those taken before FMT (P = .05). In tumor cells, 6 out of 10 patients had increased CD8-positive T-cell counts in their posttreatment biopsies (P = .057).
Three patients exhibited an objective regression of their tumor, comprising 2 partial responses and 1 complete response. All responders received FMT from the same donor. The complete responder is still in response 20 months into the trial.
Markel said the results of the study indicate that this approach in treating advanced melanoma is feasible, but multiple questions remain. He reviewed protocol considerations, such as colonoscopy versus oral capsulized FMT and eradication of the native microbiome, as key to moving this treatment method forward. Additionally, differences in donors may be indicative of responses in recipients, so methods for finding suitable donors are still uncertain.
Markel G. Treatment of refractory melanoma patients with fecal microbiota transplants and immunotherapy. Data made available as part of the virtually held National Institutes of Health–American Association of Cancer Research Cancer, Autoimmunity, and Immunology Conference; March 23-24, 2020.