Fecal Transplants May Quash Anti-PD-1 Resistance in Melanoma

A single fecal microbiota transplant (FMT) appeared to reprogram the gut microbiomes of advanced melanoma patients to overcome their primary resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy, a small single-arm phase II trial found.

In the proof-of-principle study of 16 patients, investigators at the University of Pittsburgh Hillman Cancer Center administered FMT with stool from previous good responders plus anti-PD-1 immunotherapy with pembrolizumab (Keytruda) to patients for whom previous anti-PD-1 treatment had failed.

In six of the 15 evaluable patients, the well-tolerated combination induced rapid and durable microbiota alteration, reported Diwakar Davar, MD, and Hassane M. Zarour, MD, and colleagues.

As shown in the team’s study online in Science, responders had increased abundance of taxa previously associated with response to anti-PD-1, as well as increased CD8+ T cell activation and decreased frequency of interleukin-8 expressing myeloid cells, which are associated with resistance to therapy.

“Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma,” the researchers wrote.

In the six patients with disease control, median progression-free survival and overall survival were both 14.0 months. One patient exhibited an ongoing partial response after more than 2 years and is currently on surveillance; four patients remain on treatment.

Davar said none of the usual clinical characteristics singled out FMT responders — and their pre-FMT microbiomes “were all over the place.”

There was no segregation by location of disease, sex, or age — the oldest responder was 86, the youngest was 43. “What we did see in stool samples was that every single recipient had their microbiome migrate rapidly in the direction of the donor sample phenotype, and this change was durable,” he told MedPage Today. “This suggests that microbiome modulation is key in resetting the dial in people whose cancers are not responding to therapy.”

The researchers reported that in recipients, the composition of the gut microbiota changed after a single dose in both responders and non-responders — an alteration that persisted unless a significant perturbation such as antibiotic use occurred.

FMT has also been shown to improve pancreatic cancer treatment by altering the tumor immune microenvironment.

The study participants were enrolled from June 2018 to January 2020, and all were primary refractory, defined as having no prior response to anti–PD-1 alone or combined with anticytotoxic T lymphocyte-associated protein 4 or investigational agents and having confirmed primary progressive disease.

Stool was administered colonoscopically from seven responder-donors, including four with a complete response and three with a partial response; median progression-free survival was 56 months (range 45-70). The researchers noted that interestingly, all separately collected infusates produced by the individual donors were similar to each other.

Treatment-related adverse events (AEs) were minimal, although all patients had at least one mostly low-grade event. Grade 3 AEs occurred in three patients, including two instances of fatigue and one of peripheral motor neuropathy that required hospitalization.

To evaluate the effects of FMT on gut microbiota composition in recipients and the relationship with clinical response, the researchers examined fecal samples from donors and FMT recipients before and after transplant with the help of colleagues at the National Cancer Institute.

Samples from recipients showed immunologic changes in the blood and at tumor sites suggestive of increased immune cell activation in responders and conversely increased immunosuppression in non-responders, the investigators reported.

They added that artificial intelligence linked these effects to alterations in the gut microbiome, probably due to FMT. The procedure induces persistent perturbation of the gut microbiome, which alters the microenvironment in which tumors progress.

“There are many reasons why people fail to respond to therapy, but one of them is the presence of myeloid cells, which have been associated with resistance,” Davar said. “Through the release of a cascade of cytokines and metabolites the beneficial species of bacteria appear to reduce the prevalence of these cells.”

Most of the significantly enriched taxa in responders belonged to the phyla Firmicutes and Actinobacteria, whereas most of the bacteria diminished in responders belonged to Bacteroidetes. The “good” bacterial species associated with benefit are yet to be identified, the researchers said.

Responders had distinct proteomic and metabolomic signatures, and trans-kingdom network analyses confirmed that the gut microbiome regulated these changes. The microbiota in complete-response donors exhibited higher alpha diversity than that of partial-response donors, but no significant differences were observed between donors and recipients before FMT. Nor was there a significant difference in response after FMT in patients receiving infusates from donors who had had either a complete or a partial response to anti–PD-1.

The researchers said they plan to expand this ongoing trial to 20 patients as well as launch a larger FMT trial in melanoma and other malignancies such as kidney cancer and non-small-cell lung cancer. The goal is to replace colonoscopic FMT with oral pills containing a cocktail of microbes identified as most effective for boosting immunotherapy.

Also strengthening the case for modulating the gut microbiome to improve cancer treatment, a phase I trial in the same issue of Science reported encouraging clinical responses in three immunotherapy-refractory patients given FMT.