Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients

Diwakar Davar, Amiran K. Dzutsev, John A. McCulloch, Richard R. Rodrigues, Joe Marc Chauvin, Robert M. Morrison, Richelle N. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Jonathan H. Badger, Marie Vetizou, Alicia M. Cole, Miriam R. Fernandes, Stephanie Prescott, Raquel G.F. Costa, Ascharya K. Balaji, Andrey MorgunIvan Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, Marc B. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Yana G. Najjar, Yasmine Belkaid, John M. Kirkwood, Giorgio Trinchieri, Hassane M. Zarour*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)595-602
Number of pages8
JournalScience
Volume371
Issue number6529
DOIs
StatePublished - Feb 5 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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