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

  • Science. 2021 Feb 5;371(6529):595-602. doi: 10.1126/science.abf3363.
Diwakar Davar  #  1 ,  Amiran K Dzutsev  #  2 ,  John A McCulloch  2 ,  Richard R Rodrigues  2  3 ,  Joe-Marc Chauvin  1 ,  Robert M Morrison  1 ,  Richelle N Deblasio  1 ,  Carmine Menna  1 ,  Quanquan Ding  1 ,  Ornella Pagliano  1 ,  Bochra Zidi  1 ,  Shuowen Zhang  1 ,  Jonathan H Badger  2 ,  Marie Vetizou  2 ,  Alicia M Cole  2 ,  Miriam R Fernandes  2 ,  Stephanie Prescott  2 ,  Raquel G F Costa  2 ,  Ascharya K Balaji  2 ,  Andrey Morgun  4 ,  Ivan Vujkovic-Cvijin  5 ,  Hong Wang  6 ,  Amir A Borhani  7 ,  Marc B Schwartz  8 ,  Howard M Dubner  8 ,  Scarlett J Ernst  1 ,  Amy Rose  1 ,  Yana G Najjar  1 ,  Yasmine Belkaid  5 ,  John M Kirkwood  1 ,  Giorgio Trinchieri  #  9 ,  Hassane M Zarour  #  10  11
Affiliations
  • 1. Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 2. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
  • 3. Genetics and Microbiome Core, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 4. College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.
  • 5. Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA.
  • 6. Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 7. Division of Abdominal Imaging, Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 8. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 9. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. [email protected] [email protected].
  • 10. Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA. [email protected] [email protected].
  • 11. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • # Contributed equally.
PMID: 33542131 DOI: 10.1126/science.abf3363
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.