Dr Wargo Discusses Gut Microbiota Signatures and Toxicity Link to Combined CTLA-4, PD-1 in Melanoma

Jennifer Wargo, MD, professor of Genomic Medicine and Surgical Oncology at The University of Texas MD Anderson Cancer Center, discusses a recent study which discovered an association between gut microbiome and response to checkpoint therapy in melanoma.

Transcript

Hello, my name is Dr. Jennifer Wargo, and I am a Professor of Surgical Oncology and Genomic Medicine at the MD Anderson Cancer Center. Today, it is my great honor to speak a little bit about a study that we recently published in Nature Medicine.

Treatment with immunotherapy has actually revolutionized cancer treatment, and this is now being used successfully across cancer types. However, not all patients with cancer respond to treatment with immunotherapy, and there are definitely still opportunities to improve outcomes by understanding the factors that impact immunotherapy response.

We and other groups have been focusing on this for many years, and one factor that has recently received a lot of attention is the microbiome. You might ask, "Well, what is the microbiome?" It just so turns out that, within our bodies, we have hundreds of trillions of microbes.

They actually outnumber our own normal cells. In fact, we are only about 1% human when it comes up to our genomic content. We are about 99% microbial. It goes without saying that these microbes could actually have a profound impact on our physiology.

A lot of these microbes reside in the gut, and certainly, there is evidence that gut microbes can impact immune responses and responses to cancer immunotherapy.

Now, some of the foundational studies were published a few years ago, and showed that, in preclinical mouse models, that depending on what the gut microbiome looked like in mice dictated whether or not those mice responded to cancer immunotherapy.

We and others went on and performed studies in human cohorts and actually showed that, again, we saw differential signatures in the gut microbiome of responders and non-responders to cancer immunotherapy, really providing the rationale that maybe you could just change the microbiome and make patients respond better.

Then earlier this year, there were 2 phenomenal papers that were published in science which showed that using fecal microbiota transplant from responding patients could actually reverse immunotherapy resistance in patients with cancer that were treated on immunotherapy.

This really provided the foundation that you could actually change gut microbiome and make patients respond better. We know that another issue with treatment with immunotherapy is that a lot of patients actually develop toxicity to treatment or immune-related adverse events.

We also wanted to study the gut microbiota and other factors with regard to treatment-related toxicity. To do this, we studied a cohort of patients who were treated with combined immune checkpoint blockade, targeting CTLA-4 and PD-1.

We did genomic profiling as well as immune profiling in the tumors and in the blood of patients, and actually identified some of the factors that were associated both with response as well as toxicity. These actually were in line with some of the factors that we and others had identified in the setting of treatment with single-agent therapy using anti-PD-1.

We next wanted to study the role of gut microbes in potentially mediating therapeutic toxicity. Again, we turned to this patient cohort and actually looked at the gut microbiome in patients who developed grade 3 or above immune-related adverse events.

What we found was quite striking. We actually found differences in the gut microbiome of patients who developed toxicity with a higher abundance of specific bacteria taxa, such as Bacteroides intestinalis. We then worked with Loran Zifogel, who is another leader in the microbiome worldwide, and worked with her in preclinical models to validate this finding.

Showing that, again, if we actually put Bacteroides intestinalis into mouse models, we could recapitulate this toxicity. This was really important. We actually showed that the mechanism behind this was mediated potentially through IL-1β, that you could actually block IL-1β and preserve responses, as well as abrogate toxicity.

It really led into some therapeutic avenues. Now, we know that there is a unique opportunity to actually target these gut microbes to actually abrogate treatment-related toxicity when it comes to cancer immunotherapy.

We ourselves actually performed a study a few years ago that was published in Nature Medicine that showed that, in patients who develop colitis in the setting of treatment with cancer immunotherapy, if you actually gave them a fecal transplant from a healthy donor, you could actually treat that colitis quite effectively.

It was in a small number of patients, but what this study does is actually highlights that these gut microbes actually can potentially mediate therapeutic toxicity. Can we actually target those specific gut microbes?

There is a number of different approaches that can be used to do this. Certainly, potentially targeted antibiotic approaches, maybe even phage, FMT, and other reconstitution strategies using consortia and other potential monoclonal microbial strategies.

I think it is very exciting times. I think there is certainly a lot more work to do, but I think there's a tremendous amount of promise.