This blog post is Part II in a series on the microbiome and cancer. See here for Part I.

Attempting to understand the microbiome’s role in cancer etiology for possible prevention and diagnosis of various cancers is certainly worthwhile. But since each type of cancer probably has a highly nuanced etiology, this endeavour requires the development of many specialized branches of research—and likely, many years’ worth of prospective data.

Immunotherapies started to become a viable option for treatment of cancer in the US, with the first immune checkpoint inhibitor to be FDA-approved being Yervoy (in March, 2011) for the treatment of late-stage melanoma. Since then, clinical cancer treatment has taken on a new dimension with the use of these important drugs.

By now, multiple human studies from around the world have shown differential responses to immunotherapies based on the gut microbes of a patient prior to treatment. These have led to a growing consensus that the gut microbiome is linked with immunotherapy efficacy in people with certain cancers. Certain bacterial taxa seem to distinguish responders from non-responders—although the key taxa sometimes differ from study to study.

Dr. Christine Pierce, Assistant Member at Moffitt Cancer Center, is a scientist whose research aims to integrate ‘molecular epidemiology’ and microbiome science to increase the understanding of how people with cancer respond to therapy. Dr. Pierce began her career focused on cancer etiology, on human papilloma-virus-associated cancer—but once research on the microbiome and immunology began to gather steam, she quickly also became interested in ways in which the microbiome can contribute to response to immunotherapies, and ultimately to cancer treatment outcomes in general.

Below is our Q&A with Dr. Pierce.

You’re a trained epidemiologist. What led you to study how to optimize treatment for those with cancer?

A lot of epidemiologists focus on prevention. That is actually the underlying premise of epidemiology.

But I believe it’s a little short-sighted to think that everything can be resolved through disease prevention. That would be fantastic if we could, but we need to be realistic and understand we won’t be able to prevent every case of cancer. While we would love to be able to, we simply can’t.

For the cases that don’t get prevented, we want to be able to provide some additional insight to how we may be able to optimize the outcomes of patients who do have cancer.

So cancer treatment will continue to be a field in and of itself forever presumably, but we definitely want to come up with some strategies whereby we’ll be able to modify treatments in some way to be able to improve their efficacy.

When aiming to optimize patient responses to cancer treatments, why is immunotherapy such a good place to start?

When it comes to the new immunotherapies, I think many of them are targeting these molecular pathways that are consistent from person to person. So there’s a lot more applicability across a variety of different cancers with these immunotherapies.

In terms of the role of the microbiome in response to immunotherapy, the vast majority of the studies have focused on melanoma, lung cancer, and renal cell carcinoma or kidney cancer. Historically people wouldn’t have combined research across those three cancers because there’s not a whole lot in common across the three. Etiologically, they’re quite different. But from this immunotherapeutic perspective I think it’s reasonable to examine them together because we’re more interested in the response to these immune-stimulating treatments as opposed to the development of these cancers individually.

What do microbiomes have to do with optimizing cancer immunotherapy?

Our gut microbes play an important role in our immune systems. In terms of using the microbiome, we’re thinking about ways in which we may be able to modify the microbes present in and on our bodies to promote a more suitable immune response and help enhance a therapy we already use today.

In what ways might we be able to modify our microbiomes to promote better responses to cancer immunotherapies?

I wouldn’t say we’re necessarily at a point where we can predictively modify the microbiome. [But] using probiotics is one strategy. I think we’re still learning about how well probiotics function, how stable they are over time, and whether or not what you’re consuming is actually populating the gut in a predictable way. But the idea of supplementing live bacteria of a known bacterial species or strain into the gut is one way we could modify the microbiome. So say we find a specific microbiome profile of patient enhances their treatment outcome, then those would be the strains that we would want to either be crafting in a probiotic or utilizing to populate the gut of patients, to hopefully improve the way that other patients are responding to treatment.

Fecal microbiome transplant is probably the most extreme and potentially the most effective—and that is essentially utilizing stool from a healthy donor, and re-implanting that stool into an individual to modify the existing microbiome or the existing bacteria in the stool with this healthy donor microbiome. This is something that has been used, and is actually quite efficacious in treating recurrent Clostridium difficile, or C. diff infections. It’s not yet really known whether or not it’s safe and effective for use in cancer patients. There are some studies that are ongoing, to be able to look at that. This strategy has its pros and cons… there are many aspects that we don’t yet understand, including the unintended consequences of those kinds of treatments. But where we would want to go is modifying in some predictable way the microbes we have in our gut, or somewhere else on our body, that may be able to optimize or increase the efficacy of cancer treatments.

In modifying the microbiome for better response to treatment, how important is it to know the mechanism?

I think it’s important to understand the mechanisms involved, but I don’t think that it’s necessary to fully understand the microbiome at this point. There are definitely ways in which the therapeutic angle can be approached and move things along in a clinical setting without understanding the exact mechanisms.

There are a lot of cancer treatments or therapeutics being used right now where I’d say there’s a minimal understanding of the mechanism.

Or we don’t necessarily know exactly what’s happening, or we know a little bit about what’s happening but not the entire picture, but it doesn’t mean that it’s not an effective strategy and that we’re not using it already.

Clinically, do you forsee any safety concerns when it comes to modifying the microbiome?

I think fecal microbiota transplantation (FMT) for C. diff is a good example. Say, for example, you’re able to resolve and/or cure the C. diff infection – there have been cases where the recipient of the transplant had suffered from weight gain following the transplant – I’m sure the patient was incredibly thankful that she now has a restored quality of life in being free from the C. diff infection, but at the same time there are these potential consequences that I don’t think we quite understand.

We don’t know all of these ‘side effects’—whether they’re even short-term side effects like weight gain, or long-term side effects. We don’t know how that manipulation is going to change anything over time. We also still don’t understand how our human genetics are interacting with the microbes. So even though these microbes are coming from a ‘healthy’ donor there potentially are ways in which our genetics are impacting those microbes and vice versa, to come up with some unintended consequences we haven’t even conceived of yet.

Or maybe we’ve seen it, but they’re anecdotal cases here and there, and we don’t know whether they’re going to happen frequently or rarely.

That’s the biggest issue I see in terms of the FMT-related research, the probiotic-related options, anything that’s actually going to modify the microbiome: you can affect one system but we don’t necessarily know the consequences of other systems.

Also, with an acute illness, the priority is being able to alleviate whatever condition this person is suffering from. But from a chronic perspective, say it is cancer for example, we don’t know what other systems have been modified and whether or not one or two transplants would be truly effective. We do know that the FMTs that have been conducted thus far seem to be promising in terms of modifying the immune response, and therefore if the therapeutic option for the cancer is an immunotherapy, then that is an improved therapeutic response. But whether or not these patients are going to be ‘cured’ of their chronic illness is a totally different story.

In your view, is modifying microbiome composition the most promising area in the future of cancer care?

Trying to consider ways in which we can either modify the microbiome I think is a clinically relevant and important area. But I don’t think it’s the most promising, to be honest. I think the most promising is microbial metabolomics. Most microbiome studies, with respect to cancer at least, have focused on microbial composition, whereas I believe that microbial function is not only more interesting, but it’s also likely more relevant to disease processes than just the composition alone.

Composition being what bacteria or viruses or fungi are present in a sample. But trying to examine, say the microbially-generated metabolites, those will help us better understand the functional role that these microbes are playing. Because you may have multiple microbes contributing the same function, even though they’re genetically different from one another.

So the functional role these microbes are playing within our bodies is going to provide the most information and allow us to be able to isolate and then use as a therapeutic, these metabolites, for clinical purposes.

I think that the metabolites will probably be more efficient and definitely safer than using probiotics or the fecal microbiome transplant.

This interview has been edited for clarity and length.