Certain gut bacteria are associated with response to, and toxicity from, dual checkpoint inhibition in patients with advanced melanoma, according to research published in Nature Medicine.

The researchers noted that combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with high response rates and high rates of immune-related adverse events (irAEs).  

Robust biomarkers of response to CICB are lacking, and likely up to 40% of unselected melanoma patients treated with CICB could potentially be spared from the increased risk of severe irAEs, according to the researchers.

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With this in mind, the researchers evaluated biomarkers of response and toxicity to CICB in a cohort of 77 patients with advanced cutaneous-type melanoma. The researchers also conducted parallel experiments in preclinical models.

In the patient cohort, 84% had stage IV disease, 74% had received no prior systemic therapy, 93.5% experienced irAEs, and 49% had grade 3 or higher irAEs.

Gut microbiome profiling revealed that Bacteroides intestinalis and Intestinibacter bartlettii were significantly enriched in patients who experienced grade 3 or higher irAEs (P =.009 for both).  

On the other hand, Anaerotignum lactatifermentans and Dorea formicigenerans were enriched in patients who did not experience grade 3 or higher irAEs (P =.016 and P =.06, respectively).

Experiments revealed that the gut microbiome mediated CICB-induced intestinal toxicity via upregulation of mucosal interleukin-1-beta (IL-1β) and intestinal inflammation in both patient specimens and mouse models. Furthermore, Bacteroides intestinalis and IL-1β were associated with CICB toxicity in the melanoma patients.

Pharmacologic inhibition of the IL-1 receptor (R) using anakinra, an IL-1R antagonist approved to treat rheumatoid arthritis, decreased CICB-induced intestinal inflammation in mouse models without impacting the antitumor efficacy of CICB.

The researchers also identified bacterial taxa and other biomarkers that were associated with response to CICB in the patient cohort.

Bacteroides stercoris, Parabacteroides distasonis, and Fournierella massiliensis were significantly enriched in responders (P =.03, .04, and .008, respectively). Klebsiella aerogenes and Lactobacillus rogosae were significantly enriched in nonresponders (P =.04 and .02, respectively).

Whole-exome sequencing of 26 pretreatment tumor samples showed a higher mutational burden in responders compared with nonresponders to CICB, though the difference was not significant (P =.20). However, patients who did not respond to CICB had a significantly higher burden of copy number loss compared with those who responded (P =.04).

The researchers also analyzed the distribution of CD8-positive T cells in baseline tumor biopsies. They found a higher density of CD8+ T cells in the tumors of responders compared with those of nonresponders (P =.052).

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Andrews  MC, Duong CPM, Gopalakrishnan V, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021 Aug;27(8):1432-1441. doi: 10.1038/s41591-021-01406-6.