Renal Cell Carcinoma Podcast

How Does the Gut Microbiome Impact Response to Cancer Therapy?

Sumanta Pal, MD; Jennifer Wargo, MD

Disclosures

November 02, 2022

This transcript has been edited for clarity.

Sumanta Pal, MD: Welcome to Medscape InDiscussion. My name is Monty Pal and I'm a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles. We've been doing this series on renal cell carcinoma, and I've been thrilled to cover topics ranging from adjuvant therapy to first-line treatment to metastatic disease. But what's really come up in our field, thanks to a handful of individuals, is the role and involvement of the microbiome. And to discuss that today, I'm thrilled to have Dr Jennifer Wargo from the MD Anderson Cancer Center. Dr Wargo, welcome.

Jennifer Wargo, MD: Thank you so much, Dr Pal. It's an honor to be here.

Pal: I wanted to begin by asking you a general question. You have really done a lot of groundbreaking work on the microbiome, but certainly it's been many years in coming. Can you tell us what inspired you to look at the microbiome in relation to cancer?

Wargo: Before I joined MD Anderson Cancer Center, I was on faculty at Harvard, at the Massachusetts General Hospital, and there we were studying response and resistance to different forms of cancer treatment. We stumbled across the finding that intratumoral microbes were actually contributing to therapeutic resistance to treatment with chemotherapy. That's how I got started studying the microbiome. I studied that for several years but then saw the brilliant work of Laurence Zitvogel and Tom Gajewski on the gut microbiome and began to study that.

Pal: Did that pivot you away from chemotherapy and toward immunotherapy in its relation to the microbiome? Or do you still feel that there's perhaps an influence on the microbiome with both of those treatment modalities?

Wargo: Is targeting and monitoring the microbiome the next pillar of cancer care? I think absolutely, yes. It's interesting, when I started my career at Harvard, immunotherapy wasn't working, if you will. I had studied targeted therapy and the impact of different factors on response to targeted therapy. It was through those studies that we started to study a stromal-mediated resistance, which is where we found that microbes were contributing to therapeutic resistance, in this case to treatment with chemotherapy. Since then, certainly microbes have been implicated in modulating or impacting response to all forms of cancer therapy, right? Chemotherapy, immunotherapy, different forms of cancer treatment, including radiation. And it runs the gamut, and I think you'll see the impact of microbes, both at the level of the tumor, the gut, and other sites as being critically important to virtually all forms of cancer treatment and ultimately maybe even cancer prevention.

Pal: I always think about your paper in Science back in 2018 as being one of the real pivotal papers associating immunotherapy response with the gut microbiome. I wonder if you can walk the audience through that particular manuscript and some of the data that it entailed?

Wargo: It's really interesting … microbes are a major component of the human body. If you look at the total genomic content, we're only 1% human, if you will. We have around 20,000 human genes, but we're 99% microbial. It goes without saying that these microbes are inherently modifiable and that they can have a profound impact on our physiology. A lot of these microbes sit in the gut. So, we and others hypothesized early on that these microbes in the gut could affect immunity and could impact response to cancer immunotherapy. Seeing the brilliant work of others in preclinical models, we asked the question, is this going on in patients? We had seen work presented that showed that what the gut microbes look like in mice dictates whether or not they respond to cancer treatment, cancer immunotherapy, and that you could change these microbes to make the mice respond better. We asked the question, is this happening in patients? We studied a cohort of patients with metastatic melanoma who were going on to treatment with immunotherapy, specifically anti-PD-1 [anti-programmed cell death-1]. We collected gut microbiome or fecal samples before treatment and then looked at the response to cancer immunotherapy in those patients. What we found was quite astounding. Namely, if patients had a more diverse microbiome, they were more likely to respond to treatment, which is generally associated with better overall gut health, if you will. Also, different bugs within the gut were associated with better response to cancer treatment; namely, enrichment in microbes such as Fecalibacterium, Clostridiales, and Ruminococcaceae. We took it back to a mouse model where we got fecal samples from patients who either responded or failed to respond to treatment with anti-PD-1 and recapitulated this in mice, showing that if you gave a mouse a fecal transplant from a nonresponding patient and implanted tumors, the tumors grew rapidly and failed to respond to treatment. But if you gave the mice a fecal transplant from a responding patient, the tumors grew slowly and responded quite brilliantly to treatment with immunotherapy. That is the basis on which now multiple strategies are being used to modulate gut microbes to improve responses to cancer immunotherapy. That paper was published back-to-back with papers from Tom Gajewski and Laurence Zitvogel, and additional human cohorts are really galvanizing these findings.

Pal: It certainly did. I think back to those three papers. Something that often comes up in discussion is this phenomenon of which bacteria are really driving the immunotherapy response. My interpretation is that there are slightly different bacteria across those manuscripts that seem to be driving the IO (immuno-oncology) response. Clearly these studies were done in different geographic settings, so diet might be a factor. They were done in different histology settings. I wonder if it's the disease or if it's other factors that might be driving some of those subtle differences seen across the papers.

Wargo: Great point. I think that's been one of the most difficult parts of studies on the microbiome. Everyone is looking for that one single bug that you could give to patients and make them respond to cancer immunotherapy. And it's been elusive, right? We haven't found that single bug, but what we found are some unifying characteristics. Although taxa differ across the different cohorts, there are some unifying features. I often say it's not necessarily the names of the bugs that matter, it's what they're doing. The functional aspects of these microbes matter quite a bit. In addition, I think more recent studies suggest that there are some response-associated taxa that may promote response, but there are also non-response-associated taxa that you could essentially deplete and make patients respond better. Sometimes those negatively associated bugs are easier to identify across the cohorts than the positively associated ones. Your points are well taken about different geographic settings and different diets. I always say the diet in Houston, Texas, is very different than the diet in Paris, France. I definitely think there are nuances there.

Pal: Something that comes up quite frequently in discussion in clinical practice nowadays is the role of antibiotics in the context of patients getting immunotherapy. There have been a lot of data suggesting that antibiotics can cause some degree of dysbiosis and affect IO-related outcomes. What are your perspectives on that?

Wargo: One of the earliest reports on that was from Laurence Zitvogel in her paper in Science in 2018 and it showed clearly that if patients got antibiotics just before the initiation of treatment with checkpoint blockade, they did worse. There was some skepticism at the time because it was a small cohort. Perhaps they were getting antibiotics for a certain reason, which is why they didn't have good outcomes. But now there's a large body of evidence that suggests that if you treat patients with broad-spectrum antibiotics before initiating treatment with immune checkpoint blockade, they have markedly worse outcomes. It's not to say that we shouldn't use antibiotics at all, but I think we do need to practice antibiotic stewardship and really think critically. If someone's going on to immune checkpoint blockade or is on immune checkpoint blockade and they come in with fever or inflammation, don't immediately reach for these broad-spectrum antibiotics, which may actually impact their ability to respond to the cancer treatment.

Pal: Antibiotic stewardship is certainly something we need to be practicing with this emerging data. That's such a great segue into something I wanted to talk to you about, which a lot of my patients bring up in clinic, thanks to your work. That is this concept of diet, how we might optimize response to immunotherapy, and specifically maybe you could touch on the role of fiber. It's some of the really groundbreaking work that you've done as well.

Wargo: One of the key things that we noticed in our 2018 Science paper was that a lot of the bugs that were associated with response to immunotherapy were actually fiber fermenters. We hypothesized early on that perhaps dietary interventions might augment response to immunotherapy. We studied that again in a cohort of patients, where we would collect dietary screening questionnaires in addition to getting microbiome samples when patients enrolled on to immunotherapy protocols. When we looked at the data, what we found was that if patients had sufficient dietary fiber intake, over 20 g/d, they were actually about five times more likely to respond to treatment with immunotherapy and had more prolonged survival. We recapitulated this in preclinical models where we worked with Giorgio Trinchieri at the NCI and showed that if he had mice with implanted tumors and gave them a low-fiber diet and treated them with immunotherapy, they failed to respond to treatment and also failed to activate T-cell signaling pathways. We now have dietary intervention studies underway where we give patients a high-fiber diet along with treatment with immunotherapy. We have actually seen some really brilliant responses. We give patients up to 50 g of fiber per day. We have a bionutrition corps led by Carrie Daniel-MacDougall and others, where they package delicious meals and ship them to patients. The patients love it. I think it's very well tolerated. It's seed and soil. And I think it's not only who is there in the gut, but what you're feeding them that matters.

Pal: That's so fascinating. Some of my fellows and I were discussing some of these studies that you're driving with fiber intake, and it seems like there's a handful of those out there right now. It's going to be really interesting to see how they pan out. Just on this topic of therapy to alter the microbiome, I am wondering about your thoughts on fecal microbiome transplant (FMT). There's been this really compelling series of papers that seem to suggest that FMT can turn nonresponders into responders potentially. Of course, I think FMT is marred by some issues in terms of clinical implementation, but where do you see FMT heading in the context of immunotherapy over the next decade or so?

Wargo: There were two papers that were published in Science last year, about a year or two ago, that showed really elegant findings that if you actually give a fecal transplant from a complete responder donor or from a partial responder, that can actually convert a nonresponder to a responder and, interestingly, can reduce the rates of toxicity in those patients, which was not necessarily in the high line of those papers. It was very compelling evidence. As you point out, I think an FMT (or fecal microbiota transplant) is a tractable strategy now, but it comes with risks and with nuances, right? Certainly, there have been patients who have contracted [infections with] multidrug-resistant organisms. There was a mortality. And the FDA put out a safety alert in the context of a trial where a patient was treated for C. diff colitis and died because of the FMT. It's not risk free, and you need to take a lot of points into consideration with this. Who are the optimal donors? Do we use cancer patients who have had a complete response? It's tricky, right? If you think about becoming a fecal transplant donor, the criteria or the bar is pretty high. If you now go to cancer patients and say, “okay, you have to have a certain BMI, you can't have co-morbidities,” the pool gets very shallow very quickly. Other people have said, “well, wait a second, can we actually use healthy donors as a potential source?” And Saman Maleki in Canada has been doing that with Bertrand Routy and others and really have had pretty good success. They had an ASCO abstract recently about this and have treated patients quite successfully. Fecal transplant has its complexities. The SARS-CoV-2 pandemic is another layer, right? Now we need to test patients for COVID, along with all these other potential infectious pathogens. There are known and unknown risks with FMT. There have been studies that have shown that patients can develop obesity after receiving a fecal transplant from an obese individual. There are a lot of unknown risks. Ultimately, I think FMT is an important step in the process of identifying optimal next-generation therapeutics to be able to modulate the microbiome, to enhance response, and to enhance overall immunity. I think it's a steppingstone, not an end game.

Pal: I have a lot of those same sentiments around FMT. It certainly has some promising data attached to it, but we've been thinking a lot at our institution about how to implement it, and it's really fraught with a number of very complex challenges. But we are looking forward to seeing how that moves ahead. I wanted to shift gears before we get back to therapy directed at the microbiome to another concept that you've really pioneered, which is the relationship between the microbiome in immunotherapy toxicity, not immunotherapy efficacy. I was really intrigued by a paper that you published not long ago on this topic, and I wondered if you could tell our audience a little bit about that.

Wargo: Definitely. In addition to potentially modulating improved response to therapy, there's a role for gut microbes in mediating toxicity to therapy. We studied a cohort of patients treated with combined checkpoint blockade targeting CTLA-4 [cytotoxic T lymphocyte-associated antigen] and PD-1 and showed that there were distinct microbes in the gut that were associated with toxicity. And if you could actually deplete these bugs, you could abrogate toxicity to treatment, which is really quite elegant. Other people have found similar findings. Now we're trying to work with various companies to identify therapeutics where we can actually treat patients before they get treated with immunotherapy to deplete these bugs and limit toxicity. In addition, FMT is front and center in that, where investigators have shown that, specifically for immunotherapy-associated colitis, if you give a fecal transplant from a healthy donor to patients who are refractory to steroids and biologics, you can treat that colitis effectively. This was in a small cohort, but there are ongoing studies. And if you think about these patients who have rip-roaring colitis after treatment with immunotherapy, they're pretty dysbiotic, right? They have very low diversity and their microbiomes are pretty well destroyed. Giving a healthy donor FMT can actually help quite a bit.

Pal: Absolutely. It gets me thinking about a paper in renal cell carcinoma from an Italian group that utilized a similar principle of FMT in the context of patients getting VEGF TKIs [vascular endothelial growth factor tyrosine kinase inhibitors]. That really seemed as though it ameliorated GI-related toxicity there too. I think those toxicity-ameliorating approaches with FMT are pretty far-reaching and very interesting.

Wargo: One factor I did want to mention is this unifying factor of inflammation. Dysbiosis, which is associated with cancer and with toxicity, is often associated with overall systemic inflammation, which can not only reduce response rates, but also promote toxicity. And I think that's a common thread that we're starting to see.

Pal: Is that something you think that's going to be targetable by modalities outside of FMT? Are there other strategies? I saw that your paper coalesced on certain molecules like IL-1β [interleukin-1 beta] driving some of this toxicity.

Wargo: How about IL-6? Tocilizumab, right? Can we bring that into the fold in treatment? We're running trials at MD Anderson where we combine treatment with CTLA-4 blockade, PD-1 blockade, and IL-6 blockade with tocilizumab … stay tuned. It's been effective in CAR T [chimeric antigen receptor T cell] therapy for CRS [cytokine release syndrome], and I think we're going to start to see that tocilizumab and some of the other approaches to reduce those molecules will actually become quite effective, not only in reducing toxicity, but also potentially in skewing an immune response and promoting response.

Pal: That is very interesting. I can't wait to see how that study pans out. In the last segment here related to the microbiome, I was wondering if I could just get your thoughts on how you see the field panning out in terms of more specific therapies directed at the microbiome? We've done a little bit of work related to one particular live bacterial product. Do you think that the monoclonal approach toward targeting the microbiome is going to pan out over time? It seems like it's been quite challenging thus far.

Wargo: I think FMT has proven to be effective in some studies. But again, as you point out, it's hard to do, right? There are a lot of nuances to it. Some of the earliest work with the monoclonal microbials — specifically targeting single bugs — didn't necessarily pan out too well. And why is that? I think we just didn't understand the complexities of the microbiome. But now what we're starting to see is that there are certain microbes within the gut that you can actually administer that can induce an immune response and really increase responses to cancer immunotherapy. And your group showed really elegant work in the context of ipi/nivo [ipilimumab/nivolumab] for a renal cell carcinoma, where you could give this live bacterial product and see dramatic improvements in response. I was really blown away by that. In addition to that, others have shown that there are these specific bugs that you can give in the gut that induce things like tertiary lymphoid structures [TLS] and B cells in the tumor microenvironment that are associated with the immune response. I'm a believer now. What we're starting to see is that we've started to look across cancer types at the specific taxa in the gut and their relationship to B cells and TLS in the tumor microenvironment. We're seeing unifying factors, right? I am a firm believer now that we can actually administer bugs in the gut, even next-gen probiotics, and improve responses. I will say to the audience that not all probiotics are good. We studied, in one of our recent Science papers, two commercially available probiotics and showed that they were associated with worse outcomes in preclinical models and also showed that patients who took probiotics had worse outcomes, although it wasn't statistically significant … we had low numbers. So, not all probiotics are good. Some might be okay, but they should all be tested carefully in the context of clinical trials, like you beautifully did.

Pal: That is very well said. And your enthusiasm for this approach in general is really heartening. Hopefully we can see this area of work move forward. I wanted to close by getting your perspective on something entirely different from what we've been discussing so far. You've had a really illustrious career. A lot of us have been following this amazing progress that you've been making in the microbiome, as well as multiple other avenues as it pertains to melanoma therapy in general. What's your advice to junior investigators out there? Part of the reason we introduced this little segment is that we're seeing such attrition from academia, sometimes for very good reason. But is there anything that you would suggest to young investigators out there to help them stay in the field and stay active and motivated?

Wargo: One thing is that what you do every day makes a huge difference, right? We all work very hard. But I can tell you that, having seen this from all angles, your life's work is critically important and you're helping people every day. I was in clinic yesterday and my clinic has now turned into a cancer immunotherapy survivorship clinic. It's really amazing and I'm a melanoma surgeon. Ten years ago, most of the patients who came in and had advanced melanoma wouldn't be around, but they're around now. So, what you do every day makes a difference. I think you need to love what you do and do what you love. I also think that really cultivating a network of collaborators and of like-minded people who are enthusiastic, who care, makes a big difference. I think it's also important to practice wellness and self-care to avoid burnout. Our jobs are incredibly rewarding. But I think we also need to take time for ourselves and for our families. If you can try to focus on things outside of medicine, sometimes that's quite helpful, too.

Pal: Beautifully said. What great words of wisdom for our junior faculty and trainees listening to this call. Dr. Wargo, this was a terrific podcast. Thank you so much for joining us today on InDiscussion and thank you so much to our listeners.

Resources

Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients

The Microbiome in Cancer Immunotherapy: Diagnostic Tools and Therapeutic Strategies

Commensal Bifidobacterium Promotes Antitumor Immunity and Facilitates Anti-PD-L1 Efficacy

Anticancer Immunotherapy by CTLA-4 Blockade Relies on the Gut Microbiota

Gut Microbiome Influences Efficacy of PD-1-Based Immunotherapy Against Epithelial Tumors

Dietary Fiber and Probiotics Influence the Gut Microbiome and Melanoma Immunotherapy Response

Fiber in Diet Linked to Cancer Immunotherapy Response

Fecal Microbiota Transplant Promotes Response in Immunotherapy-Refractory Melanoma Patients

Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients

Fecal Microbiota for Transplantation: Safety Alert - Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms

Fecal Microbiota Transplantation Followed by Anti–PD-1 Treatment in Patients With Advanced Melanoma

Tocilizumab, Ipilimumab, and Nivolumab for the Treatment of Advanced Melanoma, Non-Small Cell Lung Cancer, or Urothelial Carcinoma

Nivolumab plus Ipilimumab With or Without Live Bacterial Supplementation in Metastatic Renal Cell Carcinoma: A Randomized Phase 1 Trial

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