Gut Microbiome Manipulation May Facilitate Immunotherapy Response

Preclinical and observational data support a possible role for the gut microbiome in response to anti–PD-1 therapy. To investigate this clinically, Baruch and colleagues conducted a phase I trial in which 10 patients with metastatic melanoma that was refractory to anti–PD-1 were treated with antibiotics to deplete their own microbiota, followed by fecal microbiota transplantation (FMT) from one of two donors with responsive disease. The FMT was followed by reintroduction of anti–PD-1. Three patients, all of whom received transplants from the same donor, exhibited responses; two were partial responses and one was a complete response. Given the small sample size, it is unclear whether certain donor sample characteristics explain why some patients given transplants from one donor had responses whereas none of the patients with transplants from the other donor did. However, there were some differences in microbial composition of these donor samples, including a higher relative abundance of Veillonellaceae-family bacteria, which had previously been associated with favorable immunotherapy response, and lower relative abundance of Bifidobacterium bifidum, which had previously been reported to promote immune tolerance, in the more successful donor sample. Posttreatment, all patients had changes in their gut microbiota, and patients who received the more successful donor sample had greater relative abundance of Bifidobacterium adolescentis, whereas those who received the less successful sample had more Ruminococcus bromii, both of which are considered potentially favorable for immunotherapy. Changes in immune infiltrates occurred posttreatment; for example, five patients (from both donor groups) exhibited an increase in intratumoral CD8⁺ T cells, and four patients (all from the same donor) had upregulation of effector-related genes in tumor-infiltrating cells. The fecal microbiota transplantation was considered safe, with the only adverse event related to the treatment being mild, temporary bloating in one patient. Overall, the favorable safety profile and early signs of efficacy support the continued investigation of fecal microbiota transplantation to enhance immunotherapy efficacy.

Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2020 Dec 10 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.