Gut Microbiome Shows Potential as New Option for Patients With Colorectal Cancer

Patrick Wagner, MD, FACS

When it works, the use of immunotherapy offers a significant improvement in outcomes for patients with colorectal cancer. However, many patients in this population are ineligible, leaving an unmet need for more treatment options.

“[U]nlike in melanoma where many tumors are responsive to immunotherapy and are immunogenic, in colon cancer, only a fraction of colon cancers are eligible to be treated with immunotherapy,” said Patrick Wagner, MD, FACS, in an interview with Targeted Oncology^TM.

According to Wagner, surgical oncologist and director of Complex General Surgical Oncology at Allegheny Health Network Cancer Institute, considering the gut microbiome as a therapeutic intervention has the potential to provide experts with a new approach for treating patients with colorectal cancer.

Previously, a study examining the gut microbiome in patients with melanoma elicited a clear signal. Wagner notes that this discovery was as monumental as the development of checkpoint inhibitors for this patient population.

Based on the positive results of using the gut microbiome in melanoma, researchers are hopeful that the same can be seen when used in patients with colorectal cancer. However, there is limited research on the topic and more needs to be uncovered before it is known how outcomes of patients are influenced.

“The clear evidence in melanoma of changing the gut microbiome and influencing immunotherapy remotely in the body is an unmistakable signal that there’s some very profound influence of the microbiome on the immune system in a global sense. That directly would impact cancer outcomes. We’re just getting started though,” added Wagner.

In the interview, Wagner discussed the possibility of using the gut microbiome for patients with colorectal cancer, as well as his own research on the topic.

Targeted Oncology: What’s the rationale for considering the gut microbiome for therapeutic intervention?

Wagner: The best place to start is to know that the gut microbiome has been inadvertently implicated as a causative agent for colon cancer. That theory has been promulgated because it falls in line with things like H. pylori being a causative agent for gastric cancer. However, unlike with gastric cancer where there’s sort of a single organism that is highly associated with gastric cancers, which doesn’t seem to be the case with colon cancer. In other words, there’s no H. pylori for colon cancer.

That being said, there’s been a lot of interest in which bacterial species in the gut are more common in patients with cancer to try to nail down any kind of epidemiologic associations. There are a few bacteria that are overrepresented in the intestine of patients with colon cancer, including E. coli, specifically enterotoxigenic E. coli., as well as subsets of Bacteroides and Fusobacterium. There have been lots of studies along these lines, comparing patients with cancer to [those without], and seeing what differences there are in the microbiome profile. Not down to the level where we have a single agent or a proof of the causative relationship, but just associations. ’

The other thing to know is that in experimental models, it is possible to take the gut microbiome from a patient with cancer, transplant it to mice, and under the right circumstances, it can cause tumors to emerge in these mice. These are heavily altered experimental mice, ’’but nevertheless, that is the model that has been shown to transmit cancer risk with the microbiome.

In other conditions, you can do fecal transplants from 1 individual to another. Is there interest in somehow doing that down the line in oncology?

That has already been done, surprisingly, for melanoma. There have been very famous studies over the past couple of years in which therapeutic fecal transplants from patients who are responsive to immunotherapy to those who weren’t made a difference in melanoma treatment. In short, that has been tried in melanoma, which is sort of counterintuitive, because it’s not colon cancer. It’s not working in the gut, but it is transmitting some effect that happens in the intestines, presumably to the immune system, which is then reacting differently to a cancer somewhere else in the body in a therapeutic way.

Have there been other studies that show if a patient has a good microbiome environment, it translates to better immunotherapy efficacy?

I think that’s the same concept, that you can improve the efficacy of immunotherapy by modulating the gut microbiome. Because melanoma is sort of the poster child for immunotherapy treatment, ’that’s where this emerged.

Presumably, it may work in different types of cancer being treated with immunotherapy, but we’re not there yet in terms of understanding what set of cancers could be considered in this way, what the best regimen is, the details, etc. Generally, we would prefer not to take feces from 1 person and give it to another, but instead to actually understand what component of that is important. Then, [we want to] turn that into something that’s therapeutic and would come in a capsule and not in some other unsavory manner.

What is the research that you’re currently conducting?

What we’re interested in looking at is related to both of these things, but in a slightly different way. We know that unlike in melanoma, where many tumors are responsive to immunotherapy and are immunogenic, in colon cancer, only a fraction are eligible to be treated with immunotherapy. There’s something about the microenvironment of those tumors that we think of as being recognized by the immune system as foreign. Those immune cells might be recognizing the tumor as foreign but [they are] suppressed by checkpoints or other mechanisms to tone down the response or tolerate a tumor. In fact, some tumors appear to be completely invisible to the immune system, there’s not a single lymphocyte in them; or, the lymphocytes are sort of walled off or around the edges but not in the middle of the tumor where they can inflict damage on it.

The question that we have is, are the patterns of tumor-associated microbiome in those conditions different? Is there something different about the microbiome in the tumors recognized by the immune system, versus those that are tolerated by the immune system. That might help give us some clues about what is happening with the immune system and give us some targetsthat we can attempt to try to turn a patient with colon cancer that is not eligible for immunotherapy into one who is.

What are the next steps? How do we move the field forward?

If we identify themes, such as bacterial species that are always part of the mix when a tumor is recognized by the immune system, we can then attempt to dostudies where we take that bacteria, whichever it is, and use that in a targeted fashion As a form of cancer treatment.

Ultimately, [we want] a clinical trial looking at that in an advanced colon cancer population of patients who have exhausted other options, some sort of combination trial where we give a bacterial therapy to the gut along with immunotherapy novel concept for patients that have failed other standard forms of treatments in colon cancer.

What should community oncologists take away from your research?

Stay tuned, because the clear evidence in melanoma of changing the gut microbiome and influencing immunotherapy remotely in the body is an unmistakable signal that there’s some very profound influence of the microbiome on the immune system in a global sense. We hope that harnessing the influence of the microbiome on tumor immunity will lead to breakthroughs in immunotherapy in the near future.