Modulation of the Gut Microbiome to Enhance Immunotherapy Response in Metastatic Melanoma Patients: A Clinical Review

Abstract

For patients with metastatic melanoma, immunotherapy agents represent a promising treatment option, and researchers are actively seeking to identify factors that may predict a favorable response in patients. Recent studies have elucidated possible associations between the gut microbiome and the effects of immunotherapy, where variations in the gut microbiome may influence treatment response and frequency of adverse effects. In this clinical review, we describe the current literature related to the gut microbiome in the setting of immunotherapy, and we provide an overview of interventions under investigation that may modulate the gut microbiome. These interventions include fecal microbiota transplantation, probiotics, and dietary modifications.

Role of the Microbiome in Immunotherapy of Melanoma

“…The efficacy of these agents lies in their ability to reduce inhibition of the body's immune system, enabling it to better recognize and destroy cancer cells. 5 With the approval of the therapeutic ipilimumab in 2015, a new era in melanoma treatment began showing significant increases in recurrence-free survival (RFS), distant metastasis-free survival, and overall survival for stage III melanoma. 6 Approval for this immune checkpoint inhibitor therapy was followed by subsequent approvals for nivolumab, dabrafenib + trametinib, and pembrolizumab from 2017 to 2019, which have also shown significant survival impacts.…”

“…Emerging studies have reported associations between the gut microbiome and immunotherapy, suggesting that microbiological variations may influence treatment response and frequency of adverse events. 5 Response to immunotherapies in metastatic melanoma populations has been found to be associated with specific gut microbiota, in that patients with positive responses demonstrated differing microbiota composition than poor respondents. 2,5,[24][25][26][27] Alteration of microbiota has enhanced response to immunotherapy in mouse models and in recent years has even been expanded to human cohort studies.…”

“…2,5,[24][25][26][27] Alteration of microbiota has enhanced response to immunotherapy in mouse models and in recent years has even been expanded to human cohort studies. 5,28 Current human studies are investigating possible clinical interventions to alter gut microbiota to optimize response rates to immunotherapies. Some of these interventions include fecal microbiota transplantation (FMT), probiotics, and dietary modifications.…”

“…With the profound breakthrough in melanoma treatment by these immunotherapeutics, there is mounting interest in further identification of factors contributing to positive outcomes in melanoma disease-free survival. Emerging studies have reported associations between the gut microbiome and immunotherapy, suggesting that microbiological variations may influence treatment response and frequency of adverse events 5 . Response to immunotherapies in metastatic melanoma populations has been found to be associated with specific gut microbiota, in that patients with positive responses demonstrated differing microbiota composition than poor respondents 2,5,24–27 .…”

“…Current human studies are investigating possible clinical interventions to alter gut microbiota to optimize response rates to immunotherapies. Some of these interventions include fecal microbiota transplantation (FMT), probiotics, and dietary modifications 5 . Microbiota composition with specific species belonging to the Bacteroides genus in mice has been associated with efficacy using CTLA-4 blockade under the rationale that the microbiome affects interleukin 12–dependent T H 1 immune response responses to facilitate tumor control in mice and patients while also maintaining the integrity of the intestines 15 .…”