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Fecal Microbiota Transplant Overcomes Resistance to Anti–PD-1 Therapy in Melanoma Patients
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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.
abstract
This abstract is available on the publisher's site.
Access this abstract nowAnti-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.
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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 ZarourFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Oncology
These two proof-of-concept studies highlight the potential application of FMT to augment the response of cancer patients to immunotherapies. FMT has already been demonstrated to be successful in the setting of recurrent Clostridioides difficile infection and is now considered a standard-of-care therapy. Yet, the specific underlying components of FMT that contribute to favorable responses for C. difficile infection, or immunotherapy treatment in cancer patients, remain to be defined. To date there does not appear to be a defined bacterial consortium, or functional characteristics of a donor microbiota, that are consistently associated with improved immunotherapy response in cancer patients or mouse models. The challenge in the field is determining what donor and recipient features contributes to a favorable outcome for FMT or indeed an unfavorable one. Nevertheless, these studies provide exciting and compelling evidence that FMT is beneficial for a subset of cancer patients that are refractory to immunotherapy, patients that may have few alternative treatment options. The difficultly moving forward will be determining the level of mechanistic insight that is needed before incorporation of FMT more broadly in the treatment of such patients.