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Science ; 371(6529): 595-602, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33542131

RESUMO

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.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Transplante de Microbiota Fecal , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/terapia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal , Humanos , Interleucina-8/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia
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