Fecal Microbiota Transplant for Immunotherapy-Refractory Melanoma
Immunotherapy with immune checkpoint inhibitors (ICI) is the standard of care for advanced melanoma, although only around 40% of patients achieve durable survival benefit. Response to ICI therapy has been shown to be influenced not only by tumor-intrinsic mechanisms but also tumor-extrinsic factors, such as the composition of the gut microbiome. Preclinical studies in melanoma-bearing mice have shown that administration of certain gut bacteria or fecal microbiota transplantation (FMT) can improve the efficacy of anti-PD-1 therapy. In patients with cancer, the presence of specific species of gut bacteria has been associated with favorable immunotherapy response; however, the composition of an optimal gut microbiome is unknown.
A recently published single-arm, phase II study evaluated the efficacy and safety of FMT together with anti-PD-1 therapy to overcome resistance to PD-1 blockade in patients with refractory melanoma. Sixteen patients with radiographically confirmed progressive disease, who failed previous anti-PD-1 therapy alone or in combination with other agents, were treated with FMT derived from the stool of seven donor patients. Of the donor patients, four had complete response (CR) to anti-PD-1-based therapy, and three had partial response (PR), with median progression-free survival (PFS) of 56 months. A single FMT was administered via colonoscopy, along with intravenous pembrolizumab, followed by additional pembrolizumab therapy every 3 weeks until disease progression or unacceptable toxicity. Fifteen patients were evaluable for response. Clinical benefit was seen in six patients: the objective response rate (ORR) was 20% (1 CR and 2 PR) and durable stable disease (SD) lasting >12 months was reported in 3 patients (20%). At a median follow-up of 7 months, median PFS and overall survival (OS) in all patients was 3.0 and 7.0 months, respectively. However, among the six patients with disease control (CR + PR + SD), median PFS and OS were both 14.0 months; one patient with ongoing PR after >2 years is under continued observation, four patients remain on treatment, and one patient died following unrelated elective surgery. The combination of FMT and pembrolizumab was well tolerated, with minimal, mostly low-grade treatment-related adverse events. Two patients reported Grade 3 fatigue, and one patient experienced peripheral motor neuropathy that required hospitalization.
In addition, to assess the effects of FMT on gut microbiota composition in recipients in relation to anti-PD1 response, the stool samples of all donor and recipient patients were evaluated by shotgun metagenomic sequencing. The data showed that in responding PD-1-refractory patients, a single FMT successfully colonized the gut with bacteria that favored immunotherapy responsiveness and reprogrammed the tumor microenvironment to overcome primary resistance to anti-PD-1 treatment. In patients who failed to respond after FMT, several factors may be involved, including: a failure to implant successfully; the absence of vital microbiota in the FMT; an immunodeficient status; or lack of tumor immunogenicity. The investigators highlight the need for further research in larger clinical trials, which may also identify biomarkers to guide patient selection for microbiome-modulating treatment.
Davar D, et al. Science 2021; 371:595-602.