Gut Microbes May Have an Association With Toxicity Related to Combination Immune Checkpoint Inhibitors in Advanced Melanoma

Gut microbes may help to predict adverse effects and outcomes in patients with advanced melanoma who are being treated with dual immune checkpoint inhibitors.

Specific intestinal microbiota signatures appear to have an association with high-grade adverse effects (AEs) and responses to CTLA-4/anti–PD-1 combination therapy in patients with advanced melanoma, according to the results of a study published in Nature Medicine.1

Findings from the study indicated that a significantly higher level of Bacteroides intestinalis (B. intestinalis) was identified in the gut microbiota of patients with advanced melanoma who experienced toxicity from the combination immunotherapy. A higher level of B. intestinalis in the gut microbiota was associated with an elevation of mucosal IL-1β and associated inflammation, according to findings from patients and preclinical models. The preclinical models also indicated that intestinal inflammation could be reduced without impacting efficacy by inhibiting IL-1R with an agent that was approved for the treatment of rheumatoid arthritis.

“This study further highlights the importance of the gut microbiome in both response, as well as in toxicity in patients being treated with combined immune checkpoint blockade,” senior author Jennifer Wargo, MD, professor of genomic medicine and surgical oncology at MD Anderson Cancer Center, said in a press release.2 “We’re committed to understanding and addressing the significant immune-related [AEs] that tend to accompany this combination therapy, so that patients don’t have to compromise quality of life for effective cancer treatment.”

Combining immune checkpoint inhibitors has helped to boost survival across several tumor types including advanced melanoma, with CTLA-4 and PD-1 inhibitors yielding a positive number of responses. However, the regimen is frequently associated with immune-related AEs including colitis, often leading to other complications. Currently, a lack of strong biomarkers to help predict which patients will respond to treatment and which will develop severe toxicities presents a hurdle for the field. This served as the rationale for the study.

A total of 77 adult patients were included in the study, all of whom were treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors for advanced melanoma. Most patients had stage IV disease (84%) and had not undergone prior treatment with systemic therapy (74%). In response to treatment, any grade AEs occurred in 93.5% of patients, with a grade 3 AE or higher observed in 49%.

Additional findings from patients and preclinical models indicated that the bacterium Parabacteroides distansonis had an association with response to treatment. Converse to prior findings focused on single agent immune checkpoint inhibitors that target PD-1, there was not a notable difference in gut microbiome diversity between responders and non-responders.

Moreover, tumor-associated immune and genomic biomarkers of response to combination immune checkpoint inhibitors were similar to those identified for a single agent immune checkpoint blockade. Toxicity from these drugs also had an association with a more diverse peripheral T-cell presence.

Investigators concluded that these findings may offer insight into potential novel therapeutic angles for targeted toxicity associated with immune checkpoint inhibitor combination strategies.


  1. 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;27:1432-1441. doi:10.1038/s41591-021-01406-6
  2. Study identifies gut microbes associated with toxicity to combined checkpoint inhibitors in melanoma patients. News release. MD Anderson. July 8, 2021. Accessed August 17, 2021.