Microbiota Transplant Therapy Demonstrates Safety, Has No Effect on Infection for Patients with AML

Alexander Khoruts, MD

In this video, Alexander Khoruts, MD talks about his team's randomized, double-blind study, which showed that fecal microbiota transplant therapy is safe to use for patients with acute myeloid leukemia undergoing intensive chemoetherapy as well as those who have undergone a stem cell transplant. Dr Khoruts also discusses the potential of the gut microbiome as a major therapeutic target in future investigations.

Additional Resource:
Rashidi A, Ebadi M, Rehman TU, et al. Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML. Published May 26, 2023. J Clin Oncol. DOI:10.1200/JCO.22.02366


Consultant360: What was the impetus for this study? Why now?

Alexander Khoruts, MD: Well, our program in general is looking at the gut microbiome as a therapeutic target. And as most people know, the foundational disease was problems with C. difficile infections, which is a complication of antibiotic therapies and the gut microbes is the primary defense against C. difficile. And people who get antibiotics become vulnerable to this infection. And then a significant fraction of these patients suffer recurrent infections because they can't get rid of the C. difficile spores. And the repeated cycles of antibiotics just keeps decimating their microbiomes. So they're resistance or ability to protect them against C. Diff goes down with every cycle of treatment. So by repairing the gut microbiome, you break the cycle. So I think that's well established. But there is a lot of interest in gut microbiome and all kinds of other clinical applications. So one of these, which is in a similar category as C. difficile infections, is a problem experienced by patients undergoing intensive chemotherapy, perhaps by itself, or going on to a stem cell transplant.

C360: How does this study fill a current gap in our knowledge?

Dr Khoruts: So these are patients with leukemia and they undergo intensive chemotherapy to kill the cancer. Of course, it doesn't only kill the cancer, it also kills ... decimates your immune system, and by lowering your immune defenses, makes you vulnerable to all kinds of infections. And so these patients also get a lot of antibiotics, some of them prophylactic to prevent infections and some of them to treat infections. And their microbiome becomes similarly decimated, if not more so, than relative to C. diff patients. And work in other groups, like Memorial Sloan Kettering, for example, have found strong correlation between the antibiotic burden and infection burden and non-cancer mortality in these patients. And there are basic science reasons to believe that having a healthy microbiome will facilitate recovery of the gut barrier, because the microbes, the indigenous microbes provide tonic signaling for epithelial health. And also you probably want to have a healthy microbiome that wants to be friends with the host when your immune system is just developing anew after a stem cell transplant.

And so what they've noted is a correlation between antibiotic burden and infections and graft-versus-host disease. So about half of mortality associated with a stem cell transplant is so-called non-cancer mortality from infections and from graft-versus-host disease. So that's what we're trying to address, the question, will a healthier microbiome then decrease this non-cancer mortality in these very sick patients? This is not entirely a new idea. It goes back at least to 1970s when people thought, well, are there microbes in the gut that are actually protective in these kinds of situations? They found that the anaerobic fraction could play that role. And there was this race, this early idea, should we keep the microbiome normal or give the microbes back or do we stick with antibiotics? And if you do a stem cell transplant in a germ-free animal, they do better. And so the basic thinking over decades has been kill, kill, kill the microbes. And the better you're able to control the microbes, the better the outcomes are going to be.

The problem is the microbes are not static. They evolve. And so it's been an arms race. You give more antibiotics, more powerful antibiotics, and the microbes develop more antibiotic resistance. And so this has been going head and head. So we're testing this old idea, well, what if you reintroduce microbes from healthy people that don't have as much antibiotic resistance and basically facilitate recovery of the microbiome? Will that also allow for faster healing of the gut barrier in these patients who get chemotherapy? Will they experience fewer infections? There's a number of groups doing this. A lot of the inspiration came again from the C. diff infections and the success experienced there. But you can't easily translate from one indication to another. C. diff is in some way maybe thought of as a low hanging fruit in this field, although I think it's underestimated. It's not as low hanging as people believe. But basically most patients with C. diff infections have a normal gut and they have a pure antibiotic injury that needs to be repaired.

In this case that's not necessarily so. There is a mucosal injury from chemotherapy and a lot of antibiotics as well. And so how you do this, what should be the dosing regimen and what are the different ways of administration? That's all up in the air. And a problem with fecal microbial transplants has been from the beginning is just how do you standardize it? Do you just count grams of stool and how do you administer it and how do you ever know what you're doing? So I think the field started crudely like that but it's really moving toward much more standardization. So that was really I think where we came in. Our preparation is more standardized than the older versions of fecal microbial transplants. So these are purified microbiota from healthy donors. That's still a critical component is the donor program. Purified, freeze-dried, put into capsules and then administered orally, which is obviously easier than some endoscopic route of administration or nasogastric tube.

But there's still questions of, well, what is the right dose? There could be questions [inaudible 00:08:28] about donor selection still. Maybe some donors are better than others. But it's a step forward in the sense that we know we're not quantifying in terms of grams of stool. It's quantified in terms of the numbers of bacteria. They're freeze-dried. It's GMP manufactured. So it's moving in the direction that other people can reproduce. Now this was still a safety feasibility study. I think we were a little surprised that the ... well, at first I should say this is the most vulnerable population of patients you could come up with to try this therapy on. Their gut is damaged. So the gut barrier is compromised. And you're passing microbes through that. Now they're encapsulated, they're freeze-dried, so maybe they're just not quite moving around. The encapsulation is designed for C. diff, so it is generally targeting the distal portion of the gut, like colon probably, distal small bowel. Nevertheless, I think of all the patient populations, this is the most vulnerable.

C360: What were the main takeaways from the results of your study?

Dr Khoruts: And so we've demonstrated that there was no safety signal. There were many adverse events but there were just as many in the placebo as in the active group. We tested two populations. There was patients with acute myelogenous leukemia just undergoing intensive chemotherapy, as well as a larger group of patients that were undergoing stem cell transplantation. So I think the most important message is it was safe. Second is the engraftment. So we measure engraftment by doing some bayesian type computational biology to see which microbes were there from the beginning and which ones came from the donor. And actually the engraftment was less than what we normally see in C. difficile. So in the end we moved on from this study to the next phase, which is now being planned, of increasing the dose of more days that these capsules will be administered to see if we can get better engraftment. We did not see a benefit of this therapy versus placebo in the overall group, although interestingly, on subgroup analysis, the better the engraftment was, the less of these non-cancer complications were being seen. So that's somewhat encouraging to move forward.

C360: The gut microbiome seems to be a big target right now in a variety of therapeutic areas—from neurodegeneration to mental health to hormonal disorders, and more. Is the gut microbiome having its “moment”?

Dr Khoruts: Well, I think there's some truth to that. I think we have to be ... I tend to be more conservative in general and not try to over hype things. Because I think in the long term that can damage the field by giving it too much promise and then it doesn't quite live up to that. And then we give up. I mean, science often moves in incremental steps and that's probably what we need to do. But personally, when I entered the field early 2000s, what just got me standing up in my chair was work from Jeff Gordon's lab and just showing how transfers of microbiota from, let's say, obese mice into germ-free mice made them obese. And these were genetically obese mice. And what really made this possible is the ability to do deep sequencing of the metagenome and study microbes that were previously really not accessible to science. Because he had to culture individual microbe and couldn't really do that. So now we have technology to study whole microbial communities.

Now this technology is still rapidly evolving. So every six months there is something more that you can do. But that really was revolutionary and it focused the attention on the microbiome, which really it was always suspected to be there. Louis Pasteur thought that germ-free animals could not exist because it was such an important part of the body. I guess he was kind of wrong. But germ-free animals are not normal. They're not behaviorally normal. Their [inaudible 00:14:32] is not developed, their immune system is not developed. So the gut microbiome is important on a daily ... it's an integral part of the body. It's an interesting part of the body too because, unlike all other parts, it is totally open to the environment. So it's highly modifiable. It's modifiable by diet. We take antibiotics, we don't think about it, but it's like we're throwing grenades in there without thought that something bad could happen. And sometimes it does, like C. Diff. Consequences could be decade later.

There's data that early exposure to antibiotics in life correlates with inflammatory bowel disease and things later in teenage years and stuff. But bottom line, I think we accept now that the gut microbes are important in the development of the immune system, are important in the development of the nervous system, are important in our energy metabolism. Those are all topics of really modern diseases. So on the daily basis, what is the immune system seeing of the microbial world? It's mostly interacting with our own gut microbes. So they have a major part to say about calibrating the immune responses. And so we're seeing that in the field of immuno-oncology. So patients who take antibiotics may not respond as well to checkpoint immunotherapy, for example. And of course there's a lot of interest in optimizing checkpoint immunotherapy by targeting the microbiome.

There's also work in areas like autism. When I first looked at that, I'm like, "Well, that's really a pretty far stretch, gut microbes and brain." But no, actually there are interesting metabolites [inaudible 00:16:38] and others have been able to look at particular metabolites that are purely microbially derived. They can communicate with the nervous system and have effects on the brain. And there actually are plausible connections between those two. And maybe there should be because the brain is really an outgrowth of the enteric nervous system evolutionarily. So maybe that's not necessarily such a surprise. So I do think that there is going to be next areas of development. The journey from research to something that is introduced at the clinical practice is longer than most people appreciate.

There's many incremental steps in between. So while I hate to over hype the promise, I think the promise is there. I do anticipate that the journey is probably not a matter of months or a couple of years. And this is what this work is, is an example of that. We're going in step-by-step. It's a more standardized product. We have a way to ... moving in reproducible ways, modified in some desired, rational ways. Demonstrate safety, improve the dosing regimen. It's going to be more trials to get there. We may find actually that intervention, which was this early intervention, trying to prevent infections in graft-versus-host, maybe that's not the right timing. Maybe it should be done later. Maybe. But you got to do these interventional trials in order to learn something.