Abstract & Authors:展开
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.
Diwakar Davar,Amiran K Dzutsev
Giorgio Trinchieri,Hassane M Zarour
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 Morgun,Ivan 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