Point/Counter

Should screening of the gut microbiome be standard practice for patients with melanoma?

Click here to read the Cover Story, “Harnessing the gut to improve cancer outcomes.”

POINT

Yes.

We should screen the gut microbiome of our patients with melanoma. Currently, this practice is not necessary for treatment or clinical decision-making, but rather for research that could eventually lead us to the point of clinical impact.

Gino In, MD
Gino In

The gut microbiome is an incredibly rich but untapped source of information. Human DNA encodes for approximately 20,000 proteins. Conversely, the gut has a number of bacteria species and DNA that code for millions of proteins. We are learning more every day about how the gut microbiome applies to human development, physiology and pathology. From embryonic development and the maternal immunity that babies are born with, to an immune system that evolves through time in response to environment, behavior and medications, we see that these changes may be influenced by microbial species in the gut. This research is important in that it may help us understand a range of human disease, including cancer, and how it responds to immunotherapy.

For oncologists, the holy grail is to know who will respond to checkpoint inhibitors, which are still a relatively new treatment for melanoma and many other types of cancer. There were no effective treatments for melanoma until checkpoint inhibitors came out, so anything more we can learn about who will respond will be incredibly important.

Gopalakrishnan and colleagues found that increased microbial diversity in the gut, as well as the presence of specific bacterial species, were associated with responses to PD-1 checkpoint inhibition. In addition, fecal transplantation from those responding led to better responses using PD-1 inhibition among mouse melanoma models. Two other studies also found that gut microbial composition was associated with response to PD-1 inhibition, although the associated species were different across all three studies. Still, all three showed that fecal transplantation from responding patients improved responses to PD-1 inhibition in preclinical models.

This provides intriguing data and suggests that fecal transplantation may be an option for patients receiving checkpoint inhibitors. We’ve seen that fecal transplants can be effective in C. difficile and in inflammatory bowel disease. There also are ongoing clinical trials in melanoma, but those approaches are not yet ready for prime time.

We need to do further research and continue to study the gut microbiome. In addition to identifying the relevant microbial species, ongoing studies are needed to analyze the gut proteome, metabolome and transcriptome, as well. The functional aspects of these microbial species remain unknown, meaning we don’t know what exactly these bacteria are doing and what mechanisms they use to affect immunotherapy and other treatments. The impact of other nonbacterial microbes and how they affect the host immune system and tumor microenvironment also require study.

There is a lot more that may be learned through screening of the gut microbiome. Screening the gut microbiome can be done easily because fecal samples are easy to collect, so why wouldn’t we?

References:

Gopalakrishnan V, et al. Science. 2018;doi:10.1126/science.aan4236.

Matson V, et al. Science. 2018;doi:10.1126/science.aao3290.

Routy B, et al. Science. 2018;doi:10.1126/science.aan3706.

Gino In, MD, is associate professor of medicine at Keck School of Medicine at University of Southern California. He can be reached at gino.in@med.usc.edu. Disclosure: In reports advisory/consultant roles with Boehringer Ingelheim, Bristol-Myers Squibb, Castle Biosciences and Novartis.

COUNTER

No.

At this time, we should not be screening the stool of our patients with melanoma as part of standard practice.

Sunandana Chandra, MD, MS
Sunandana Chandra

Preclinical and clinical studies have shown the importance of the gut microbiome in patients with melanoma. There have been a limited number of prospective trials in which patients with metastatic melanoma who are treated with immunotherapy have been studied in order to understand the diversity and impact of the gut microbiome.

There appear to be distinct differences in gut microbiome diversity and composition among patients who respond to immunotherapy and those who do not. Further, studies seem to suggest that the gut microbiome may be predictive of which patients develop an immune-mediated colitis. However, gut inflammation as a result of immune-mediated processes can alter the composition of the gut microbiota, so it may be imperative to define the microbiota before the colitis develops.

Research from Gopalakrishnan and colleagues shows that there was a distinct difference in the microbiome of patients who responded to immunotherapy. Among 112 patients who received anti-PD-1 antibody therapy, increased gut microbiome diversity was associated with increased response to therapy. Specific bacterial species (Clostridiales, Ruminococcaceae or Faecalibacterium) in the gut appeared associated with increased CD4-positive and CD8-positive T cells in the systemic circulation; conversely, Bacteroidales in the gut appeared associated with increased inhibitory T regulatory cells and myeloid-derived suppressor cells. Further, when germ-free mice underwent a fecal microbiota transplantation from human responders, there was increased tumor reduction in the mice compared with fecal microbiota transplantation from nonresponders.

This study suggests that having a favorable gut microbiome may be a predictive biomarker for immunotherapy efficacy. It is important to note that the numbers of responders and nonresponders are small in this trial. However, it is clear that more research is warranted for the identification of gut microbiota in patients with melanoma. This knowledge and understanding truly would be practice changing and may lead to better therapeutic measures to modulate the gut microbiome to prevent or minimize immune-mediated toxicities or increase immunotherapy efficacy.

However, until we have a better understanding of these factors, we should not routinely (off trial) screen stool microbiome of patients with melanoma, as it may not be clinically beneficial or change patient outcomes.

Reference:

Gopalakrishnan V, et al. Science. 2018;doi:10.1126/science.aan4236.

Sunandana Chandra, MD, MS, is assistant professor of medicine at Feinberg School of Medicine at Northwestern University. She can be reached at sunandana.chandra@northwestern.edu. Disclosure: Chandra reports no relevant financial disclosures.

Click here to read the Cover Story, “Harnessing the gut to improve cancer outcomes.”

POINT

Yes.

We should screen the gut microbiome of our patients with melanoma. Currently, this practice is not necessary for treatment or clinical decision-making, but rather for research that could eventually lead us to the point of clinical impact.

Gino In, MD
Gino In

The gut microbiome is an incredibly rich but untapped source of information. Human DNA encodes for approximately 20,000 proteins. Conversely, the gut has a number of bacteria species and DNA that code for millions of proteins. We are learning more every day about how the gut microbiome applies to human development, physiology and pathology. From embryonic development and the maternal immunity that babies are born with, to an immune system that evolves through time in response to environment, behavior and medications, we see that these changes may be influenced by microbial species in the gut. This research is important in that it may help us understand a range of human disease, including cancer, and how it responds to immunotherapy.

For oncologists, the holy grail is to know who will respond to checkpoint inhibitors, which are still a relatively new treatment for melanoma and many other types of cancer. There were no effective treatments for melanoma until checkpoint inhibitors came out, so anything more we can learn about who will respond will be incredibly important.

Gopalakrishnan and colleagues found that increased microbial diversity in the gut, as well as the presence of specific bacterial species, were associated with responses to PD-1 checkpoint inhibition. In addition, fecal transplantation from those responding led to better responses using PD-1 inhibition among mouse melanoma models. Two other studies also found that gut microbial composition was associated with response to PD-1 inhibition, although the associated species were different across all three studies. Still, all three showed that fecal transplantation from responding patients improved responses to PD-1 inhibition in preclinical models.

This provides intriguing data and suggests that fecal transplantation may be an option for patients receiving checkpoint inhibitors. We’ve seen that fecal transplants can be effective in C. difficile and in inflammatory bowel disease. There also are ongoing clinical trials in melanoma, but those approaches are not yet ready for prime time.

We need to do further research and continue to study the gut microbiome. In addition to identifying the relevant microbial species, ongoing studies are needed to analyze the gut proteome, metabolome and transcriptome, as well. The functional aspects of these microbial species remain unknown, meaning we don’t know what exactly these bacteria are doing and what mechanisms they use to affect immunotherapy and other treatments. The impact of other nonbacterial microbes and how they affect the host immune system and tumor microenvironment also require study.

There is a lot more that may be learned through screening of the gut microbiome. Screening the gut microbiome can be done easily because fecal samples are easy to collect, so why wouldn’t we?

References:

Gopalakrishnan V, et al. Science. 2018;doi:10.1126/science.aan4236.

Matson V, et al. Science. 2018;doi:10.1126/science.aao3290.

Routy B, et al. Science. 2018;doi:10.1126/science.aan3706.

Gino In, MD, is associate professor of medicine at Keck School of Medicine at University of Southern California. He can be reached at gino.in@med.usc.edu. Disclosure: In reports advisory/consultant roles with Boehringer Ingelheim, Bristol-Myers Squibb, Castle Biosciences and Novartis.

PAGE BREAK

COUNTER

No.

At this time, we should not be screening the stool of our patients with melanoma as part of standard practice.

Sunandana Chandra, MD, MS
Sunandana Chandra

Preclinical and clinical studies have shown the importance of the gut microbiome in patients with melanoma. There have been a limited number of prospective trials in which patients with metastatic melanoma who are treated with immunotherapy have been studied in order to understand the diversity and impact of the gut microbiome.

There appear to be distinct differences in gut microbiome diversity and composition among patients who respond to immunotherapy and those who do not. Further, studies seem to suggest that the gut microbiome may be predictive of which patients develop an immune-mediated colitis. However, gut inflammation as a result of immune-mediated processes can alter the composition of the gut microbiota, so it may be imperative to define the microbiota before the colitis develops.

Research from Gopalakrishnan and colleagues shows that there was a distinct difference in the microbiome of patients who responded to immunotherapy. Among 112 patients who received anti-PD-1 antibody therapy, increased gut microbiome diversity was associated with increased response to therapy. Specific bacterial species (Clostridiales, Ruminococcaceae or Faecalibacterium) in the gut appeared associated with increased CD4-positive and CD8-positive T cells in the systemic circulation; conversely, Bacteroidales in the gut appeared associated with increased inhibitory T regulatory cells and myeloid-derived suppressor cells. Further, when germ-free mice underwent a fecal microbiota transplantation from human responders, there was increased tumor reduction in the mice compared with fecal microbiota transplantation from nonresponders.

This study suggests that having a favorable gut microbiome may be a predictive biomarker for immunotherapy efficacy. It is important to note that the numbers of responders and nonresponders are small in this trial. However, it is clear that more research is warranted for the identification of gut microbiota in patients with melanoma. This knowledge and understanding truly would be practice changing and may lead to better therapeutic measures to modulate the gut microbiome to prevent or minimize immune-mediated toxicities or increase immunotherapy efficacy.

However, until we have a better understanding of these factors, we should not routinely (off trial) screen stool microbiome of patients with melanoma, as it may not be clinically beneficial or change patient outcomes.

Reference:

Gopalakrishnan V, et al. Science. 2018;doi:10.1126/science.aan4236.

Sunandana Chandra, MD, MS, is assistant professor of medicine at Feinberg School of Medicine at Northwestern University. She can be reached at sunandana.chandra@northwestern.edu. Disclosure: Chandra reports no relevant financial disclosures.

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