Stool Swap Overcomes PD-1 Resistance

Fecal transplants can make immunotherapy-refractory melanomas sensitive to checkpoint blockade. The finding, from a pair of small clinical trials—the first of their kind—highlights the potential of manipulating gut bacteria to boost response rates to anti–PD-1 agents (Science 2021;371:595–602; Science 2021;371:602–9). Yet, the best strategy for modulating the microbiome—whether with capsules or colonoscopies, fecal material from healthy donors or cancer survivors, or even fecal matter versus lab-grown microbes—remains a matter of active debate.

“The results from both groups are really exciting,” says John Lenehan, MD, of London Regional Cancer Program in Canada, who is leading a trial to evaluate fecal microbial transplantation (FMT) in patients with treatment-naive melanoma (J Immunother Cancer 2020; 8(Suppl 1): A11–A12). “There is much that we don't yet know,” he adds, “and hopefully we will learn a great deal from the similarities and differences in our approaches.”

In the two reports, both groups obtained stool samples from donors who experienced durable responses to anti–PD-1 drugs, such as nivolumab (Opdivo; Bristol Myers Squibb) and pembrolizumab (Keytruda; Merck), and administered the fecal matter to patients with refractory metastatic disease. There were some notable methodologic differences, though.

One group, led by researchers at the NCI and the University of Pittsburgh Medical Center in Pennsylvania, performed the FMT by colonoscopy on the same day that they administered an initial course of pembrolizumab to patients, followed by additional immunotherapy until disease progression or intolerable toxicity. None of the recipients had responded to prior anti–PD-1 therapy. The combination was well tolerated and produced clinical benefits in six of 15 individuals: One had a complete response (CR), two had partial responses (PR), and three experienced stable disease lasting a year or longer.

The other group, led by clinicians at the Sheba Medical Center in Tel-HaShomer, Israel, prescribed antibiotics before treatment to clear native intestinal microflora. Focusing on patients who developed resistance to anti–PD-1 therapy, they administered FMT via both ends of the GI tract—by colonoscopy and feces-filled capsules—for 2 weeks before starting patients on nivolumab. Of the 10 individuals treated, one had a CR and two experienced PRs lasting at least 6 months.

Both studies detailed how the stool swaps led to favorable shifts in cytotoxic T-cell activation and other aspects of anticancer immunity, both inside the tumors and out. Trial participants who benefited from FMT also experienced upticks in the number of bacterial taxa previously linked with responses to anti–PD-1 therapy in observational studies, but the change in microbial abundance was statistically significant only in the U.S. study.

“The transplant induced a major and persistent change in the microbiota,” says Giorgio Trinchieri, MD, chief of the NCI's Laboratory of Integrative Cancer Immunology, who co-led the U.S. study. The two trials together, he adds, provide “the first proof of concept that you can actually treat the patients [with FMT] and change their response to therapy.”

Still, he adds, “I don't think the future will be fecal transplant.” Instead, many researchers anticipate that rationally designed cocktails of bacteria—or even single lab-grown strains—will supplant stool samples as the microbial products of choice to pair with checkpoint inhibitors.

“A cultivated consortium has an enormous number of advantages over donor fecal material in terms of safety, reproducibility, scalability, and tunability,” says Bryan Coburn, MD, PhD, of Toronto General Hospital Research Institute in Canada (N Engl J Med 2019;381:2043–50).

Coburn and his collaborators are evaluating one such defined formulation of bacteria from NuBiyota. Other microbial mixtures from Seres Therapeutics and Vedanta Biosciences are also in clinical development. –Elie Dolgin