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Microbiome Matters: Interview With Dr. Christian Jobin

[00:00:00] John Marshall, MD: I told you I was going to have the smartest people on the planet to interview, and I've got one of them here who has joined us. He survived the storm that just went through the middle of Florida, so we're grateful for that. Probably stirred up the local microbiome. This is Christian Jobin.

[00:00:25] Christian Jobin, PhD: They moved the gators around, so they have to relocate the gators.

[00:00:28] John Marshall, MD: Oh, wow. But that's good.

So, thank you for joining us on our discussion in Oncology Unscripted. So, you and I don't have a script. Tell us about microbiome. I've heard you speak. I know what you're doing. But, you know, so many of us don't

[00:00:45] Christian Jobin, PhD: thanks for having me here. It's a great pleasure to talk to you, and to try to bring some education to microbiome. A couple of little definitions here. So, microbiome, if you look at the definition, it's the assembly of genes within a microbial community, but often people think that microbiome is a bacteria, a group of bacteria, but it's an ecosystem. So, you have bacteria, fungi, yeast, and viruses. So, it's a collective assembly of microorganisms that lives a different location, right? So, on us, inside us, everywhere. So, I'm not going to throw numbers, but they are there.

They are there from the beginning of your life, acquired through a vertical transmission, birth canal or skin acquisition, throughout your childhood. Your sample, you geta  petri dish. You build your microbiome, and you maintain it, or not, depending on your lifestyle. Right? So, it's an amazing collection of microorganisms that responds to environment, stress, diet, and exercise. All things that we foresee as important to prevent cancer, and/or to maintain good health. So, they are part of that habit.

And, and how do they do that? These microorganisms, you will think that, oh, it's just a bunch of microorganisms. They don't do that much. No, they do a lot, right? They occupy a territory within your system. If you think about the gut, they would occupy you know, trillions of microorganisms in there, and they are producing various molecules. They are responding to the diet you give them and to prevent infection. So, all of this is an active contribution to your health and the balance of this community maybe put you at risk of developing cancer or non-responding to therapeutics, for example.

[00:02:45] John Marshall, MD: So many people think they know how to build a microbiome. I always joke that CVS has an aisle where you can buy probiotics, right? And then what's the right way to live? What's the right health? What do we know? You know, in medical school, I've been saying that we don't really learn anything about this because we thought it didn't matter. But now that we, we're still not changing the curriculum, by the way, the current curriculum doesn't have much on this today.

[00:03:11] Christian Jobin, PhD: True. That's a shame.

[00:03:13] John Marshall, MD: But do we know how to measure it? Do we know how to make a good one?

[00:03:16] Christian Jobin, PhD: Yeah, we know how to measure it. We don't have a precise definition of what is good as a microbiome. Like this is the microbiome you should have. If you don't have this one, you're in danger of developing XYZ disease. Not really. We could screen a microbiome at the genomic level from different locations. So, most of the time, the non-invasive will be feces, but you could take saliva and say, oh, this microbiome may be associated with head and neck cancer, or the microbiome here in the feces associated with, you know, early onset colorectal cancer, for example. We kind of try to build this, but we're not ready for prime time, but that's the long view on that.

Could we re-establish your microbiome once you have that information that this microbiome is damaged? I say damaged because I think microbiome is like an organ. So, it's damaged because, you know, maybe inadequate lifestyles, maybe episode of XYZ antibiotic treatment. So, it's damaged. How do we damage that? To your point, if you go to CVS and buy probiotics because they say it will maintain a good health function, there's no data. No data on that. We don't know what we're buying because they are not FDA, you know, scrutinized.

[00:04:35] John Marshall, MD: Could I take this a step further from my own stupid concept is I always describe these to patients and to my audiences as, it's a rainforest, the soil in a rainforest, or it's what the conditions that allow for a coral reef, the complexity is needed. And what that CVS bottle is doing is if I plowed the rain forest, and I'm planting a bunch of pine trees. It's not A rain forest, right? It's a row of pine trees.

[00:05:03] Christian Jobin, PhD: I love that image. You, you get it exactly. We call, you know, there's metrics in microbiome, characteristics, we'll say diversity, alpha, beta diversity, and the more diverse, most of the time, the healthier your microbiome is so that, if in a disease case the microbiome is less diverse. The way to fix that is not to put billions of bacteria that are from, Bifidobacteria genera or Lactobacilli genera it's not the way. Some have multiple components into their probiotic, their cells, it will be maybe six of them, but this is a very tiny segment of diversity. So it doesn't fix diversity if you are in a diversity low, state of microbiome. Prebiotics, fermentable food, so food that maintains your ecosystem, are a better way to go than trying to put something that you buy in a bottle that you don't even know if they are alive. You don't even know the quantity of them. You don't even know if they will stick or just pass. So, it's magic thinking.

[00:06:14] John Marshall, MD: I want to ask two angles on this one. You mentioned earlier about identifying people at risk. The observation in my world, early colon cancer, 90 percent of these patients are having rectosigmoid tumors. So not normal distribution of tumors. So, I've thought there must be some sort of local environmental thing through the microbiome that's happening there. I do want to talk about your thoughts about immunotherapy in the microbiome, but let's start with that one example, what's your thinking about detecting risk in that patient population.

[00:06:53] Christian Jobin, PhD: No, absolutely. So, you know, the survey of microbiome is very critical. So, if you take a microbiome from feces, that is an assemble of microorganisms that pass through, you know, elimination of feces. So, they could be coming from, you know, the proximal colon all the way, so you don't know where they are. If it's a rectal colon, and you could sample it, you have a local idea of what's going on there, that could be more reflective of the immune environment. Because if I want it to be sampled in terms of relationship between microbes and cancer, it will be the engagement of the immune system.

These microorganisms are fully equipped with different molecules and surface proteins that, the hosts, us, could detect through millions of years of evolution. So, we have a way to know, hey, these microbes are there, and here's how I'm going to respond to it. So, it impacts the immune environment locally, they are within that tumor. And having information of who is there may be very critical for a therapeutic intervention, for example, in terms of rectal cancer.

[00:08:08] John Marshall, MD: Skip to the other side quickly about, you know, your concept of the role that the microbiome is playing in therapeutics with our immune therapies. There's a lot of talk, a lot of action in that space. Part of what we covered here with our papers. Any thoughts as to what's going on there?

[00:08:24] Christian Jobin, PhD: beside that, it's extremely exciting time and we're collecting data throughout the world. we don't have a precise understanding

[00:08:31] John Marshall, MD: I want to make sure everybody hears you say that so many people come in sure of what they're doing, and I don't think we are. Are we?

[00:08:39] Christian Jobin, PhD: No, we don't. patients are extremely well educated. They know what's going on. They go, you know, they know the microbiome. They could search. They see clinical trials. They see some data. They see the promise and they think they could get a new way to get treatment.

[00:08:56] But, I mean, we're experimental all the way in. We don't have a precise understanding. The hope is that eventually by dissecting and slicing the microbiome, we will have a better idea of who is contributing to a partnership with a XYZ drug. So, we will have a precise way to help the patient if the patient is missing these microorganisms, for example, or a molecule that is produced by the bacteria to adjuvant with therapeutics. But we're just not there. Not there.

[00:09:30] John Marshall, MD: I have one comment. I'm really hopeful that bourbon is good for your microbiome, but we can talk about that at the end of the day today.

[00:09:39] But I have a fun question for you, is that, you know, I have some religion in my heart and soul. And my soul is the question. So, I keep thinking about where the soul resides. I keep thinking about the microbiome and these creatures and this ecosystem that lives within us. And increasingly, I think the soul is within our microbiome. What's your vote on that?

[00:10:02] Christian Jobin, PhD: So, listen to your microbiome and guidance for your life.

[00:10:07] John Marshall, MD: So, you know, we think about what we feel, we feel it in our gut.

[00:10:13] Christian Jobin, PhD: Yes.

[00:10:15] John Marshall, MD: That’s why I'm saying that's where it must be.

[00:10:16] Christian Jobin, PhD: That gut feeling. Yeah, absolutely.

[00:10:17] John Marshall, MD: Exactly. All right.  Dr. Christian Jobin, I thank you so much for your time. I know things are busy for all of us right now, but we really appreciate your coming and sharing your knowledge, and excitement, quite honestly, about this field. So, we really appreciate you joining us.

[00:10:31] Christian Jobin, PhD: Thank you Dr. Marshall. It was a pleasure.

How Does The Microbiome Augment Immunotherapy? Interview With Dr. Sumantra Pal

[00:10:34] John Marshall, MD: I promised you all a great set of interviews, and you're going to be very glad you clicked on this one to hear Dr. Monty Powell talk about his science, which is why we're here. I'm dressed like a real doctor today. I got a badge. I've been seeing patients today downstairs. He's a real doctor, too. And so, we thought we would pretend to be our real doctor selves and talk to you about how microbiome could be a tool in treating cancers.

[00:11:00] And so I'm going to hand it over to you, just to let you tell the gang. What's your sort of thought process was how you've begun to apply it and some of the results you're seeing in your clinical trials.

[00:11:14] Sumanta K. Pal, MD: it's a really long story and I'll try to sort of abbreviate it. First of all, thanks for having me. You know, this whole premise of the microbiome wasn't really anything on my radar until one of my biostatisticians approached me, in fact, and this is the craziest story, but my biostatistician had a lot of friends in the agriculture industry. And there, you know, we manipulate the microbiome left and right to increase the longevity of livestock to, you know, get crops growing the right way, and he was asking me, why don't you do this in humans? And so about a decade plus ago, we started doing some basic studies, looking at the stool microbiome in patients with kidney cancer, which is principally what I focus on in the clinics. and then this series of papers came out, Science and Nature, really sort of linking the composition of the gut microbiome to immunotherapy and that's when we really decided to sort of take a step back and say, could we potentially do something to influence the gut in a way that has the activity with immunotherapy.

[00:12:11] John Marshall, MD: It’s sort of like religion or believers and non-believers and a lot of this to me spins down to, we don't really know what we're believing in, what microbiome is. I was talking earlier about how it's, you know, even in our own GI tracts, my world, it's probably a bunch of different pools or lakes that are connected. And so the microbiome in pool one might not be the same in pool four. and they may not even talk to each other. And so, you know, in terms of measuring and, and then believing scientifically that this is important . Did you run into much issue as you tried to push this forward as a clinician in a clinical trial scenario?

[00:12:50] Sumanta K. Pal, MD: you know, I will say that we're just in a state of the science where, you know, we just don't have complete definitions of the microbiome across the board. You know, these studies that have linked immunotherapy to outcomes, with respect to the microbiome have all been done a different tumor types. They've all pointed to different bacteria, frankly, that are associated with improved clinical outcomes. In melanoma, it's been Bifidobacterium, Ruminococcus and kidney and lung cancer, Akkermansia. So, I think that's induced a little bit of skepticism. But, you know, I’ve slowly become a believer over time.

[00:13:21] John Marshall, MD: So, tell us what, in the end, what you decided to do and maybe some of the early results that you're seeing.

[00:13:26] Sumanta K. Pal, MD: So, this also comes from a contact at my hospital, the first case of biostatistician, in this case, the chair of our immunology department, Peter Lee, MD. He's been working with a company in Japan, that has a product called CBM588. This is a product that's been used for generations in Japan to just take care of general GI ailments.

[00:13:44] and people in Japan apparently swear by it. You know, you can buy it at the equivalent of a local Rite Aid or what have you out there. Very safe product. And it's comprised of a single strain of Clostridium butyricum. There have been a lot of preclinical studies and some retrospective studies suggesting that it can boost the impact of immunotherapy. So we've done at this point, two small randomized trials, and these are tiny studies, 30 patients each 20 in the experimental arm, 10 of the control arm, in each of these, but we've shown that CBM588 can augment the activity of nivolumab and ipilimumab, one of the typical regimens we use up front in kidney cancer and also cabozantinib and nivolumab, another common frontline regimen.

[00:14:22] So we're actually trying to push this forward. There’s a trial that may be rolling out in SWOG in the next year or two. It's going to look prospectively at any TKI/IO or IO/IO regimen plus or minus CBM. So that's going to hopefully be the proof of the pudding.

[00:14:38] John Marshall, MD: It's awesome. And I'm assuming well-tolerated. Do you notice a tox difference when you're given the probiotic?

[00:14:43] Sumanta K. Pal, MD: No, we were hoping actually that we would mitigate some toxicity by using it. We haven't really seen that. We've just seen this really interesting signal in terms of boosted efficacy.

[00:14:51] John Marshall, MD That's wild. Give me a theory, I mean, when, when you've had a couple of glasses of wine, why is this working?

[00:14:57] Sumanta K. Pal, MD: You know, both of our studies were published in Nature Medicine and usually Nature Medicine requires very sort of rich mechanistic data and we, we supplied that, you know, we had pretty rich bacterium profiling studies with metabolic pathways. If I'm being totally honest with you, at the end of the day, we really didn't identify a single sort of MOA for what we were seeing with CBM588.

I do believe that there's probably some truth to the possibility that these bacteria get into the lower gut and start releasing short chain fatty acids into the circulation. And these short chain fatty acids are really the ones that we think are driving the improved T-cell response that you get with immunotherapy. This is something that's really challenging to prove because these short chain fatty acids are very labile. We're talking about butyrate or propionate. These are in and out of the system very quickly, but you know, it's something that we're working on within our team now.

[00:15:48] John Marshall, MD: Are you seeing the same thing in your cancers that I see in mine where we're seeing responses in lung but not liver and different regions, or is it not really playing out for you?

[00:15:59] Sumanta K. Pal, MD: you know, it's a brilliant question. In fact, I'm working with one of our junior colorectal colleagues at City of Hope to design a study where we're looking at the difference between liver and non-liver metastasis in that specific context. I haven't really sort of seen that as much in renal cell, but we're at such a nascent stage in this field. I definitely think it's worth looking at.

[00:16:19] John Marshall, MD: Hell, you're further along than the rest of us, so don't give me that we're in a nascent stage. At least you're further up. You got one flight of stairs up when the rest of us are just trying to decide which stairs to walk up. Let me ask you one sort of really bizarre question. I've been, lately, I don't know if you're a religious man at all, but I've been increasingly thinking that the microbiome is where the soul resides. Where are you on that stance, a pro or con on that?

[00:16:42] Sumanta K. Pal, MD: Oh my gosh, you know, we're going to have to do some sequencing studies and figure it out. I just, I don't know.

[00:16:48] John Marshall, MD: Well, to me, it makes sense that this is this other creature that lives inside of us that we don't really understand and talks to us, but we're not listening to all that well. And so, to me, it fits very nicely for the way God communicates with us all through our microbiome and our soul.

Dr. Monty Powell, just the world's expert in kidney cancer and really an innovator in bringing this kind of novel approach of trying to harness and influence our microbiomes to improve outcomes from our patients. I know you're a busy man and I know catching you this afternoon was not easy. So, I appreciate it very much. Dr. Monty Powell.

[00:17:24] What an amazing subject the microbiome is. I'm convinced that there's so many important things that we are going to discover over the next few years in this space. Yep, better therapies for cancer patients, yet better ways to live to prevent disease and maybe discover why kids get diabetes. Who knows what we're going to figure out as we uncover the microbiome. Join us next time on Oncology Unscripted with John Marshall to find out what's cool and happening ahead.

 [00:17:58]

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This transcript has been lightly edited for clarity.