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In this study, 15 patients with progressive metastatic melanoma and no response to prior anti–PD-1 therapy were treated with fecal microbiota transplantation (FMT) from 7 donors who had a partial or complete response to ICI and pembrolizumab. There were 3 partial responses, and 3 patients achieved stable disease. Responders showed distinct proteomic and metabolomic features, and the gut microbiome was shown to regulate these changes.
The combination of FMT plus anti–PD-1 therapy induces changes in the gut microbiome and tumor microenvironment, which allows some patients to overcome previous resistance to anti–PD-1 therapy.
– Paul J. Hampel, MD
This abstract is available on the publisher's site.
Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. 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.
Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients
Science 2021 Feb 05;371(6529)595-602, D Davar, AK Dzutsev, JA McCulloch, RR Rodrigues, JM Chauvin, RM Morrison, RN Deblasio, C Menna, Q Ding, O Pagliano, B Zidi, S Zhang, JH Badger, M Vetizou, AM Cole, MR Fernandes, S Prescott, RGF Costa, AK Balaji, A Morgun, I Vujkovic-Cvijin, H Wang, AA Borhani, MB Schwartz, HM Dubner, SJ Ernst, A Rose, YG Najjar, Y Belkaid, JM Kirkwood, G Trinchieri, HM Zarour