As stirrings rise of a cancer “moonshot” focused on the relationship between the human microbiome and cancer, City of Hope’s Marcel van den Brink says this is the perfect time for such an influx of support.
“This is the right time to have those folks who are studying microbiome and cancer and have moved now into, I think, a critical phase where they have the first lines of evidence that it can be used for therapeutic purposes also,” van den Brink said at a summit brought together by City of Hope.
The symposium, which took place on the City of Hope campus in Duarte, CA, May 13, was co-sponsored by NIH.
Also attending were the leaders of six other cancer research institutions, who, at a luncheon with HHS Secretary Robert F. Kennedy Jr., discussed the opportunities in having the government bring together a program that would emphasize large, randomized clinical trials focused on the role of the microbiome in cancer treatment and prevention.
A story about the symposium—which was attended by leaders of six NCI-designated cancer centers, NIH Director Jay Bhattacharya, NCI Chief Science Advisor George Sigounas, and HHS’s Kennedy appears in this issue.
“We have plenty of evidence, in retrospective fashion, in preclinical fashion, but now also with first-in-man trials—relatively small cohorts, sometimes even just a few patients—that a manipulation of the gut microbiome can improve outcomes,” van den Brink said. “I really feel we’re now at a critical juncture where we need to find some more funding to be able to do diet studies, fecal transplant studies, any kind of therapy that targets the gut microbiome to improve outcomes. We are there now, but we need funding for that.”
Van den Brink has seen this before:
“This has been the history, basically, of allogeneic transplant, the field that I grew up in; right? I always say allogeneic bone marrow transplantation has been mostly an academic effort supported every so often by maybe a small biotech or pharma impulse, an antifungal drug or something like that, but all the big steps were funded through academia and through NIH.
“And here we are now, bigger than ever, and it’s a lifesaving therapy for MDS and AML,” he said. “So, it just shows you that sometimes you cannot only depend on biotech and pharma to take something into the clinic.”
How is a moonshot different from a run-of-the-mill government-sponsored research program?
Van den Brink said he hopes the microbiome moonshot will bypass bureaucracy and instead rapidly bring together top scientists and institutions to tackle the problem with urgency.
“I hope that I’m right about that sentiment, that it will have a stronger sense of urgency, but still, that it will follow the same format of what I know of moonshots, that you try to bring as fast as possible the best of the best in a certain field from all over the country together and that’s the dialogue that we hope we can start now with HHS and with NIH and, of course, NCI,” van den Brink said.
Van den Brink spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
This conversation is available as a video.
Paul Goldberg: Well, Dr. van den Brink, thank you so much for finding the time to talk with me. I had a couple of questions about your symposium on the microbiome in cancer last week. I guess the most important question is, why did you put it together? Why did you decide to do this?
Marcel van den Brink: We thought it was a very timely moment to do this for a number of reasons. First of all, and most of all, if you think about where the field is of microbiome research, thanks to the Human Microbiome Project One and [Human Microbiome Project] Two—those are the ones that started in 2006 and ran until 2017 or so—we’ve learned a lot about the different microbes, bacteria on different sites within your body, what kind of communities, et cetera.
The initial phase of that project was basically taxonomy and knowing where all the bugs are.
The second one started to look at diseases, but mostly within diabetes and IBD [irritable bowel disease], little bit of cancer, but not that much.
And what we thought was that this is the right time to have those folks, who are studying microbiome and cancer and have moved now into a critical phase where they have the first lines of evidence that can be used for therapeutic purposes, gather in a meeting, organized and co-sponsored with the NIH, and see what we learned during that meeting, and think about what we can do next.
This is the classic format that you well know from many NIH topics that you start with a gathering of the experts within a certain field. You listen to them for a whole day during a meeting. and then after that you start thinking, “Okay, based upon what we learn now and what is needed to move the field forward, let’s think about an RFA.”
That was our initial thinking, and we were very happy that [NIH Director] Jay Bhattacharya was willing to co-sponsor this with me, and that we could find leading experts within the field, bringing this into cancer and into a therapy from all over the country.
Well, the most dramatic moment there was when Secretary Kennedy used the word “moonshot” to describe the NIH and HHS plans for research in the microbiome.
And the word “moonshot” rhymes with another M word, which is “money.”
So, did you expect that to be said, or did that surprise you as much as it surprised everybody else?
MvdB: No, I did not see that coming.
As I said already, the original plan that we had was to use this as a starting point to discuss an RFA.
And I was, of course, very pleased when both Robert F. Kennedy and Jay Bhattacharya, in their talking points, ended with announcing that they would support a moonshot.
All right. I guess, sitting there and listening, I started wondering what is the difference with the moonshot and the regular NIH or NCI program.
I actually do not have an answer. Do you?
MvdB: I don’t have a direct answer yet, because, of course, now we will use this as a starting point to develop that with them.
But if I think back of other types of moonshots, it always felt that there was a greater sense of urgency with organizing it, that it wouldn’t go through sort of traditional formats, with a lot of waiting for funding, or having an application, and then reviews, and then on a couple of months go by until you finally know who is going to be part of it and who’s going to be funded.
So, I hope that I’m right about that sentiment, that it will have a stronger sense of urgency, but still, that it will follow the same format of what I know of moonshots, that you try to bring as fast as possible the best of the best in a certain field from all over the country together and that’s the dialogue that we hope we can start now with HHS and with NIH and, of course, NCI.
You mentioned the two phases of the microbiome project, Phase One and Phase Two, and in the second phase there was a little meeting on cancer—actually a big meeting on cancer—but really not a whole lot was done on cancer in that context.
What is the state of knowledge about the microbiome in cancer and what do we know now that we didn’t know then and what can NCI do that it’s not doing, or that it should be doing, or could be doing?
MvdB: First of all, let me be very clear that both the NIH, as I pointed out already, and the NCI over the years have funded in many different ways projects within this field; right?
But what we haven’t had over the last seven or eight years or so is one of these bigger projects, like the Human Microbiome Project One and Two.
Nobody can argue with the fact that we have a lot of problems within this country with our diet, but how do we turn it into actual measures and actual therapies?
Where are we now within the field? There are certain areas that are really developing towards therapeutic use. First of all, a lot of work initially (and I’ve been part of that also) has gone to try to understand the gut microbiome as an immune modulator when it comes to efficacy and toxicity of critical cancer immune therapy, such as checkpoint blockade, CAR cells, allogeneic transplants.
And there we have plenty of evidence, in retrospective fashion, in preclinical fashion, but now also with first-in-man trials—relatively small cohorts, sometimes even just a few patients—that a manipulation of the gut microbiome can improve outcomes.
I really feel we’re now at a critical juncture where we need to find some more funding to be able to do diet studies, fecal transplant studies, any kind of therapy that targets the gut microbiome to improve outcomes. We are there now, but we need funding for that.
It is difficult at the moment to find funding elsewhere for those kind of trials, because many of these trials would depend on biotech and pharma, as they do in most cancer therapies, but it’s difficult if you think about diet to depend on biotech and pharma, because there’s not much IP there; right?
If you’re going to say we’re going to do a high fiber diet, for instance, how can you generate revenue from such a strategy? So, that makes it really critical for NIH to really step in as they have done in a number of areas where biotech and pharma cannot really be the drivers of translating something from bench to bedside.
This has been the history, basically, of allogeneic transplant, the field that I grew up in; right? I always say allogeneic bone marrow transplantation has been mostly an academic effort supported every so often by maybe a small biotech or pharma impulse, an antifungal drug or something like that, but all the big steps were funded through academia and through NIH.
And here we are now, bigger than ever, and it’s a lifesaving therapy for MDS and AML.
So, it just shows you that sometimes you cannot only depend on biotech and pharma to take something into the clinic.
So, all that political juice that was flowing down there at that meeting is a recognition that there is a very important purpose for NIH and government-funded cancer research.
MvdB: Absolutely. Yes. I would argue that, but certainly when it comes to diet, which we all realize is a very important part of our health.
Nobody can argue with the fact that we have a lot of problems within this country with our diet, but how do we turn it into actual measures and actual therapies?
Within the field of cancer, I have pointed out, and others also, during a patient’s journey, pretty much every patient at a certain point is going to ask their doctor, “What should I be eating? What should I be doing with my diet?”
And the answers that we give are bland.
The answers are mostly, “Well, have a diverse diet.”
We mostly give answers that are based upon what we know from cardiovascular studies when it comes to diet. So, we need to do better. We need to be able to give our patients much better answers, and we can only do that if we do trials, if we do studies, if we have scientific rigor; right?
That’s what we do in academia. That is how we develop therapies. But in this case, it’s going to be difficult to do that with biotech and pharma.
Well, it’s impossible, but what do you actually say to your patients when they ask you that question?
MvdB: I do exactly the same thing at the moment as most other doctors—diverse food.
Yes, I will talk about fiber. I will talk about vegetables. We have learned by now that the neutropenic diet, you might still know about that that is not based on anything; right?
This is what we would be telling transplant patients and many cancer patients for years, that they should stay far from any fresh fruits or vegetables, because that was dangerous. You might get fungi from that, et cetera. We have learned, thanks to studies, by the way, that that risk is not there, and that it’s actually good for patients to have fruits and vegetables, as you might have guessed.
So there’s a lot of these kind of myths also around a diet, mostly fueled by a lack of real knowledge and a lack of real science. So, to a certain extent, we try to do the best we can with limited knowledge.
We owe it to our patients to do better, to study this with much more rigor, and develop real trials based upon what we’ve learned about the value of diets; right?
Within this context of the gut microbiome, we know—and those are studies that I have done and that others have done—that if you change your diet, within 48 hours you change the makeup of your gut microbiome.
So, it’s really a therapeutic tool that we have.
Well, you had a whole day long symposium, which I greatly enjoyed and found enlightening, and these were all small studies, but some of them were pretty incredible, like the whole idea that the actual tumor may be a very small part of a much larger picture, and that’s kind of eye-opening to think about that.
MvdB: Well, I think if you look at the evolution, how we think about cancer therapies; right? Which of course started initially with zooming in on every tumor cell and we do genomic profiling, and so on. And that’s now bread and butter of how we analyze cancers and how we develop therapies.
Then we started to learn there’s more to it. It’s the tumor microenvironment specifically for immunotherapies where the tumor microenvironment can be immunosuppressive.
And now we’re starting to draw ever wider circles.
We understand that actually the germline is also incredibly important, because that might tell you something about the immune makeup of a certain person.
Now you can go even one step further, if you realize that any human is more than just his or her own cells, but also all of these microbes that live inside and outside of you; right?
You have as many microbes as you have cells. So, these ever-wider circles of what is relevant for a cancer give you more chances and opportunities to develop therapies.
Can we talk about the clinical studies that you envision? Are these large randomized trials of dietary interventions? What would be the first hypothesis you’d like to test?
MvdB: Well, I don’t want to be prescriptive about that; right?
I have some ideas that I would like to do within my own field, but if you do a moonshot, you want to listen to many different views of many different people, how they want to go forward.
So, I think you should open it up for different ways that you want to tackle this. Can be from diet to fecal transplants to capsules with certain microbes. There are certain nutrients that you could give that could work also.
You could focus on some of the metabolites that we have found to be beneficial that are being generated by bacteria, butyrate being the classic one that is already in some trials. So, I think you got to leave that open to the various centers and the various scientists who will weigh in.
Within the field of cancer, I have pointed out, and others also, during a patient’s journey, pretty much every patient at a certain point is going to ask their doctor, ‘What should I be eating? What should I be doing with my diet?’ And the answers that we give are bland. The answers are mostly, ‘Well, have a diverse diet.’
I think where you can help in the context of a moonshot is give some basics, create a template, how you can do it. For instance, of course, we want to know that in all cases, what the microbiome looks like beforehand and after and afterwards.
So, come up with clear ways that you’re going to screen the microbiome, probably with shotgun sequencing methods. You can add more things to that; right?
We’re now learning how you can also do transcriptomics of these bacteria. You want to probably come up with a metabolic profiling in all of these patients. So, you can give all of the surrounding critical variables. You could standardize that, you can come up with best-in-class methods for that, for the correlative science, and you can help with the classic ways of setting up phase I, phase II, and phase III trials.
I don’t have to tell you that that is an area that is constantly changing also, where they’re coming with newer and faster ways maybe to do a phase I study or a phase II study.
You can think about what kind of toxicity studies you want to do. You can think about how you want to monitor patients’ symptoms, patient-reported outcomes.
So, there’s a whole series of templates and correlates that you can pretty much standardize and then you make it much easier for somebody to plug their specific trial about a diet modification or a microbe that they want to give or an ecosystem of multiple bacteria and test that.
So, that is how I would look at it.
But I guess the next thing is the, or actually is it the next thing? George Sigounas mentioned that sometime around next fall there would be a meeting with Tony Letai as co-chair.
What is the process then? Do we kind of hibernate till that meeting in September or is there-
MvdB: I hope not. Hibernation during summer is anyway difficult, but maybe you have ways of doing that.
So, what we hope is that in the next days already that we would discuss with HHS, NCI, and NIH how to go forward, but I can’t give you a real roadmap here yet. I mean, this is all still so fresh; right?
We just had this whole symposium, and are just extremely pleased with the commitment to a moonshot, but how that is going to be formulated, what the timeline is for that, I think nobody knows that yet.
So, stay tuned for that one. You will be the first. We’ll let you know.
Please do.
This is just an observation on my part, that this whole thing was brought together by City of Hope. Is that correct?
And then the invitation to NIH and so forth. So, the exercise of leadership was yours.
MvdB: That is correct.
My dear friend and colleague Harlan Levine put a lot of effort in this, and we’ve been working on this since last fall, with multiple meetings both in Washington or by Zoom with leaders in HHS, NIH, and NCI.
And yes, we were extremely pleased with how interested they were and that they were willing to sponsor this whole meeting and so on and so on. It was a very fruitful, very collaborative effort.
So, there was this luncheon with the cancer center directors and Kennedy and you were there. What was the role of center directors of the centers actually in this project and what about the NCTN groups and NCORPs and so forth?
MvdB: Yeah. So I was not at the luncheon. The luncheon was only with the presidents of the various cancer centers or cancer center leaders, a small group.
The way that we did this, we thought if Robert F. Kennedy is coming to our campus, let’s use this also as a way to create an opportunity for leaders of the major cancer centers to have an open dialogue with him.
That’s all that I know because I wasn’t part of it, but I hear that it went well, and that the various cancer center leaders really touched on issues that are relevant at the moment for cancer patients and cancer care and cancer research.
It’s an interesting concept that there’s the wide broad support for this from other centers, but I’m wondering about the groups, the NCTN groups and NCORPs. And I would think that they would be playing some role in this.
MvdB: That might very well be, but it’s really for me too early to say anything about that.
So, again, when it comes to the planning of this moonshot, I know you want to hear more of where we are, but this just happened. We are just starting to think about how we are going to develop this. I’m just over the moon is probably the right way to say that both the NIH director and Robert F. Kennedy made this pledge.
I’ll be covering the NCI workshop for sure. So, that’s probably the next step, but there could be something inbetween. I’m sure there will be, since we’re not going to be hibernating.
MvdB: It’s hard to do during summer. Yes.
Well, thank you so much.
MvdB: Thank you.
