Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients
By D. Davar, A. Dzutsev, J. McCulloch, R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, R. Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano and 22 more. Science, 2021
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New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa 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, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science, this issue p. 602, p. 595; see also p. 573 Resistance to immunotherapy can be overcome using fecal microbiota transplantation for patients with metastatic melanoma. 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.
Subfields: Epidemiology, Infectious Diseases, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/21b43a5081416b508183aaa7397a5d5d1b93144f
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Citations in the corpus
- Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022, result): “The results of two phase 1 clinical studies NCT03341143 and NCT03353402 showed responder-derived FMT effectively relieved the resistance to α-PD-1/PD-L1 in some melanoma patients, having implications for modulating gut microbiota in cancer immunotherapy [26, 317].”
- Hallmarks of Cancer: New Dimensions. (2022, background): “Provisional proof-of-concept has come from recent studies demonstrating restored efficacy to immunotherapy following transplants of fecal microbiota from therapyresponsive patients into patients with melanoma who had progressed during prior treatment with immune checkpoint blockade (97, 98).”
- The microbiome and human cancer (2021, background): “Completion of microbiotamodulation trials are additionally crucial for guiding clinical applications and increasing the cancer therapy armamentarium (142), with new evidence demonstrating that modulation of the gut microbiota using FMT in immunotherapy-refractory melanoma patients is associated with”