The Medical Innovators Interview with Professor Brant Inman | July 2022
From superheated nanoparticles to intravesical therapy and barriers to change in bladder-cancer treatment – there’s plenty of food for thought in our July Medical Innovators interview, with Combat’s Guy Cooper in conversation with Brant Inman, Professor of Urology at the Duke Cancer Institute, Duke University, North Carolina.
Professor Inman gained his medical degree from the University of Alberta in Edmonton, completing his urology residency at Université Laval in Québec and his urologic oncology fellowship at the Mayo Clinic. He is on the board of the Society of Urologic Oncology Clinical Trials Consortium, a member of the Research Council and Research Grants and Investigator Support Committee of the American Urological Association, and a past member of the National Comprehensive Cancer Network bladder and penile cancer panel.
His research interests are in the field of urologic oncology, including clinical trials and translational research related to bladder, prostate and kidney cancer. The author of more than 150 peer-reviewed articles and 17 book chapters, he has received multiple awards for his research. In 2007 Prof Inman published the first study describing the role of the PD-L1 protein in bladder cancer, which eventually led to the approval of PD-L1 inhibitor immunotherapy for bladder cancer.
It was a pleasure to meet you at the AUA2022 Annual Meeting in May, Professor Inman, and to see you moderating some of the sessions. It would be great to start today’s interview by looking at your specific areas of research and interest.
My main clinical interest is bladder cancer, although I also manage kidney, prostate, testicular and penile cancer. But my tumour focus is bladder cancer and my research tends to align with that. I have mainly research projects in bladder cancer and in prostate cancer. My area of interest is in immunology and drug delivery, and I do research in hyperthermia or heating with respect to the bladder.
There are two different kinds of research that I do. The first is clinical research or clinical trials – things we’re directly applying in humans. And then there’s the translational research, the things I’m doing in the laboratory, where I’m either taking things that have been discovered at the very early stages and trying to translate that to humans, or taking something we’ve observed in humans and trying to figure out how it works in the lab.
I have several lines of research that I think are pretty interesting. One is a grant-funded project looking at a new way of heating tumours in the body. With engineering colleagues at Duke, we’ve developed some nanoparticles that have unique properties – when you shine light on them, they heat up really, really, really hot. And we’ve been able to label these particles with molecules that home them into tumours so we can heat cancers. And this results in some pretty special immune responses which help eradicate tumours elsewhere in the body that haven’t even been treated – what’s known as an abscopal effect. We’re working on understanding how this is happening by dissecting the immune system and trying to amplify these types of immune responses, so that perhaps the treatment of a tumour over here could lead to the response of a tumour elsewhere.
Do you see that as something with predominantly urologic applications, or could it be for any tumour in the body as long as you can put the correct markers on it to hunt out that tumour?
I think it could occur pretty much anywhere. The idea is that if we can find a dominant lesion or tumour, treat it and induce a potent immune response, then hopefully the body’s immune system would be good enough to not only clean up the remnants of the tumour we’ve destroyed in that location, but then migrate elsewhere in the body and destroy smaller metastases that we may not even have seen. That’s our hope.
We’ve had some discussions with your colleagues about abscopal effects. We’re obsessed with tumour remnants that have been missed in the bladder, and of course there’s a whole other world of metastatic disease which we tend to see in our abdominal work. So if you can treat something so distant from the action of treatment, that’s an amazing development. I’m an orthopaedic surgeon by training, so my knowledge of immunology is workable, but if it gets too complicated, I may pass out due to the academic strain of it all. Our HIVEC treatment with Combat BRS heats the chemo to 43°C so we’re not damaging healthy cells, but you say these nanoparticles get super-hot?
They do – up to 1200°C. The difference, though, is that with nanoparticles we’re dealing with extremely small foci of heating, so we can heat the inside of cells and cause minimal damage around the tissue. It’s kind of like a precision-heating method. And it’s interesting that even though we get to what we call ablative temperatures, about 60-65°C, leading to cell death in the tumour, we still see sub-lethal hyperthermia in the periphery surrounding the tumour. These are temperatures in the 40-45°C range that are not killing cells but leading to some interesting changes in the stuff surrounding the tumour.
What’s interesting is that many people have shown, in several different contexts, that the milieu surrounding the tumour is often very immune-rich. It’s almost like soldiers besieging a castle, and the castle walls are so strong that they can’t get in. Our idea is if you can break down those walls, bomb the fort, that empowers the soldiers to get inside.
So you take a fairly brutal approach to the tumour itself, but on such a nano level that your local thermal damage is low, and it also increases the efficacy of the already existing immune response?
Yeah, that’s true. And one of the ways we’re manipulating that is by combining nanoparticle heating with different immune manipulations – in particular, things like PD-L1 and PD-L1 targeted therapies. But we have other strategies as well that we’re using to try and amplify this halo effect or immune response to the injury.
And what about other nanoparticle technologies? When you say you’re working with the PD-L1 immune pathways, are you looking at very targeted drug delivery through such small particles?
So far, no. This is definitely possible, though. Right now we’ve linked different homing molecules to our particles that allow them to actually bind to specific immune receptors present in tumour microenvironments. But we haven’t labelled or targeted them with toxic agents to deliver drug locally. That being said, we have worked in the past with a number of different drugs, including liposomal forms.
This was sort of where my brain was going, because we also did some work with a liposomal-coated systemic drug which was then locally activated. I wondered if there was something still there. There’s nothing available for patients today to my knowledge. But it’s still an area that sounds very worthwhile.
We did a fair amount of work on this type of thing where we have thermally sensitive liposomes which contain chemotherapies that aren’t released at regular body temperature. So you could include this. And really, the chemo drug would leech out very, very, very slowly over time from these relatively tight liposomes. But if that same liposome was flowing in a blood vessel that happened to be in a tumour, and that tumour happened to be heated, it could release the drug at very high rates. And what this would lead to is rapid accumulation of chemotherapy at much higher doses than typically possible within a tumour, which would also minimise the distant off-target deposition of the chemo drug. This would be helpful if you had a tumour without a high burden of metastasis elsewhere and you were trying to ablate it – a good example would be muscle-invasive bladder cancer.
Where we want to try and spare the bladder instead of removing it, one way to do that may be to heat the bladder while giving systemic drug that would concentrate at extremely high doses within the cancer. This would allow us perhaps to better treat those tumours. Unfortunately, we don’t have a good, large animal model to test this right now. The mice and rats with good bladder-cancer models are just too small to test this kind of heating reliability, because we don’t have a device we can use in them that would be translatable to humans. We need larger animal models in order to test this before being able to do something like that in humans, I think.
The other problem has been the availability of pharmaceutical partners with reliable product streams that we could use. And there are a number of different chemotherapies that could be or have been packaged within these liposomes, things like doxorubicin and cisplatin – commonly used drugs that are very effective for bladder cancer. So this could be an interesting area in the future for bladder sparing.
Is there anything in phase three trial at the moment that’s coming close to being available for patients?
Well, in terms of bladder sparing, unfortunately almost everything we’ve seen so far rarely surpasses a complete response rate of about 40-50%. So with the best drug treatments we have for muscle-invasive – chemo, chemo-packaged with immune therapy, that kind of stuff – where the bladder is removed, we see no tumour in 40-50% of patients. Whether that’s durable is another question.
It’s possible that we wilt the tumour but it just grows back later. I think we’re ripe for some innovation in that space. If I had a telescope to look into the future, I would sure hope to see we were removing far fewer bladders than we are now. It’s a very morbid operation with substantial risk and long-term effects. It’s probably better than dying for most patients, right? But it’s not the panacea, and those of us who do a lot of bladder removals should all acknowledge that.
This is not a great operation to have. None of us would want to have it on ourselves unless it was absolutely required. And if we could get to a state where we could kill the tumour without the need for radical surgery, boy would that ever be a boon for our patients. I think that’s where we’re headed, frankly. And I would hope that in 20 or 30 years we’ll be able to get away without removing the bladder of at least some of the patients where we currently would be.
I was sort of nudging the conversation in that direction but my years working as a local radio DJ have obviously not been wasted with my ability to segue. So for non-muscle-invasive disease that has failed primary therapy, whether BCG or something else, there are a number of new drugs around that you allude to in your last answer. But if I can be blunt, none of them work. Where are we going with that? What’s going to happen with BCG failure? We have some new drugs, and they still don’t work. What are we going to do?
Well, you know, it’s interesting. I think your question needs to rewind the clock even further. The problem isn’t so much BCG failures. The problem is, why are these tumours coming back in the first place? And part of that has to do with the way that we manage the very first tumour. To me, it makes absolutely no sense that we would put a scope inside someone’s bladder, chop up a cancer into little chunks, rinse it around in the bladder and expect it not to come back. That’s dumb. We don’t do that with any other cancer, right? The whole concept of treating cancers is to remove the tumour intact within margin. This is a very Halstedian principle of surgery. You need to respect the oncologic boundaries of the tumour.
Yet somehow in non-invasive bladder cancers, we find it reasonable and acceptable to do otherwise. And I think that’s the root problem. So with the first of the new trials coming out now, I think the innovation is going to be, “Okay, why are we doing that?” Why don’t we do some form of intravesical therapy first, try and kill whatever weeds we can on the vine right then and there, and clean up what’s left with TUR? Maybe we’ll have fewer seeding events. Maybe we’ll trigger better immune responses so that our body, when it’s eradicating the cancer that’s been killed by the chemotherapy prior to TURBT, will be able then to mount some sort of immunity to help reduce the risk of recurrence down the road? Kind of like an autovaccination.
I think the future in that space will be in looking at how we’re managing this from the start, instead of waiting and developing at the end of the line when nothing works. We need to start doing things that make a lot more sense and see if we can find ways to avoid the TURBT altogether, or at least to make it much less likely to spread tumours around the bladder. So treating the tumour better is one of the problems.
The other problem is the field defect. Many patients who develop bladder cancer have been exposed to carcinogenic compounds, typically through tobacco smoke but also occupationally or environmentally, that are leading to these tumours. And those exposures occur throughout the urogenital system, right? The entirety of the renal pelvis, ureters, bladder and urethra get exposed to the same thing – the bladder just holds it for a longer period of time, so we presume the reason that the tumours occur more frequently in the bladder than in the other locations is because these carcinogens are soaking into the bladder for much longer – until you take a pee – whereas with the other places they are just moving through.
So how do we eradicate the field? How do we get rid of those cancers that are about to form in other locations? It would be like skin cancer – most people who have sun-exposed skin get skin cancer here and then there. Yet it’s not because that first one has spread. It’s because the entirety of the skin’s surface has been affected.
So I’m thinking there’s got to be a way that, from the start, we can better identify and eradicate those pre-malignant areas in the field. And we’re getting there. For instance, some of our advanced endoscopy methods that are now available, like narrow-band imaging to a lesser degree, and blue light to a higher degree, are enabling us to identify areas in the bladder that we never used to see. And I suspect those are just the start. If I take my 20-year telescope, I suspect we’ll have molecular imaging of some nature in the bladder that will allow us to identify and eradicate those parts of the bladder.
For example, I can imagine a laser-based resurfacing process where we look in the bladder after the tumours have been killed, and whatever’s left – which you can’t see with the naked eye but you can with some sort of advanced imaging – you could laser off, so that a new layer of bladder could form there. I could imagine things like this happening so that we can reduce the likelihood of recurrence due to the field defect. So if we can improve that as well as the quality of the first resection or removal of the tumour, I think we’re going to dramatically impact everything that happens subsequent to that – which is recurrences, then needing BCG, then failure of BCG, then failure of agent number two, then failure of agent number three, ultimately resulting in a shrivelled-up bladder with cancer that needs a cystectomy.
It strikes me that urologists have become innovators in the prostate – there is always a new toy for ablating with hot things, cold things, steam, voodoo, something else – and they have the most famous medical innovation of the last 20 years, the surgical robot, to do prostatectomies and cystectomies with. Yet in the bladder, we’re still doing exactly the same that we were 30 years ago. I would love to be able to persuade urologists to do neoadjuvant work, because there are some excellent results with our technology that show two-thirds of the patients have complete T0 response. And two-thirds of them are still without any tumour five years down the line. But it seems that in the bladder world it’s difficult to get the jobbing urologist to move away from just doing BCG, mitomycin and cystectomy. Neoadjuvant is a difficult concept. Heat has been a difficult concept. How are we going to move this along?
Well, I think what convinces everybody is large, randomised trials and guidelines – that’s the standard in all of medicine for changing the standard of care. So what’s lacking is a good, large, randomised trial where patients are treated the usual way or given neoadjuvant therapy followed by TUR, if needed. Now the problem is that those kinds of clinical trials are expensive, and they need to be large – we’re probably talking a 1000-patient clinical trial or at least 500, depending on what your endpoint is. And the other thing is they read out over time.
So, depending on your population, it’s going to be a two to five-year interval for discovering whether or not it actually works. And for many smaller companies, like Combat, that time horizon can be prohibitive. You know, if you’re a large pharma, you can withstand a prolonged period of waiting to know if your thing is better. But for smaller companies that need to continually innovate and show progress, that’s much more challenging, I think. So for me, these are predominantly the barriers.
The other thing is that it’s been really hard in bladder cancer to get funding from governmental agencies. Despite this being the fourth most common cancer in men, and being one of the most expensive cancers because of the frequent recurrences, it’s relatively underfunded compared to almost every other cancer. So I think that’s a subsequent problem. It’s not a sexy cancer. I don’t know why.
It’s always been the case. You’d think prostate cancer would be equally taboo because of the issues of potency and continence around it, yet it’s commonly spoken about – in the UK there’s a little silver man pin badge sold by the Prostate Cancer UK that people wear to raise awareness. But with bladder, I don’t know if it’s because people are embarrassed, but it’s massively under-represented.
I agree. And I’m not sure exactly why. We don’t have that many famous people coming out about having it, either. If those who did have it spoke up and discussed it, that would probably help to some degree. But it’s something that hopefully is being addressed.
One of the great things that’s come in the last ten years in the US has been the Bladder Cancer Advocacy Network. Diane Quale and her husband John started it in 2005, after his diagnosis in 2000. Unfortunately, John passed from metastatic bladder cancer in 2008, but she’s kept the torch running. It’s really changed the grassroots movement for bladder cancer in the US and I think it’s helped spark similar movements elsewhere in the world. And I think that’s very important. As the patient advocacy groups become stronger, we’ve noticed there are better opportunities in the US – still not enough, but better opportunities to get funding in this field.
Yes, we’ve seen the same here in the UK, with excellent work being done by friends of ours at Fight Bladder Cancer and Action Bladder Cancer, and these groups tend to be founded by somebody who is suffering from it. Patients are becoming more educated and more vocal. And let us hope that this drives change. When I first started working in this area six or seven years ago, I was amazed that the concept of neoadjunctive was not being adopted globally. It’s seen as a real outlier, so I’m heartened that an innovator such as yourself believes it’s the way forward. If you had a squillion dollars of research money in your lap now at Duke and could only spend it on one thing that’s going to be transformational in the uro-oncology area, what would that be?
Hmm. Well, that’s a good question. While the biggest threat to life is muscle-invasive bladder cancer, the largest community impact in my opinion is non-muscle-invasive. That’s because 75% of patients with bladder cancer have non-muscle invasive. They’re the ones who are consuming most of the healthcare resources to help stop their tumours from coming back. So I would probably spend it on trying to reduce the recurrence rate for that kind of cancer.
If I had a second pick, it would be at bladder sparing – how to eradicate muscle-invasive bladder cancer while leaving the bladder intact and maintaining its function to some reasonable degree. Because, as you know, a lot of the times when we do bladder sparing, the bladder the patient is left with is far from desirable. And sometimes it’s so bad that they beg us to remove it because it just can’t hold anything and they’re incontinent. So I think those would be my two wishes. And if I had a lot of money, you could probably tackle both. So I think that’s what I would investigate.
Looking through your telescope into the future again, what’s happening with the bladder cancer patient’s pathway in 2050?
Well, let’s start with endoscopy. I think cystoscopy will be dramatically different, and probably much less invasive. I think we’re going to be gathering much more information – I envision an era where we’ll have bladder maps, where our endoscopes will be like the Google car when it drives down the road, takes images of the street, and then reconstructs a 3D map. I think we’re going to do this in the bladder. And I think we’re going to overlay information on this map, such as what molecules are expressed, so we’re going to have molecular imaging too. I definitely think that’s coming.
I’d also imagine that when we’re treating tumours, it will be far more precise. I think we will be good at identifying pre-cancerous areas and eradicating them before they form tumours. And I think that when we get into patients who start with muscle-invasive bladder cancer, we’re going to have ways of saving their bladder and minimising the morbidity of therapy. I think that’s where we’re headed.
It would be nice to see that we’re doing less or certainly doing things less often, doing a better job of them when we do them, and working towards not having to do them in the first place. This idea, as you say, of treating the field is a wonderful way to look at it.
The other thing is prevention. I strongly suspect we’re going to have information in the next decade or two about environmental causes of bladder cancer that we didn’t expect – perhaps the containers we serve our food in or things in the environment. I collaborate with veterinarians in the local veterinary school because dogs also get bladder cancer. And I suspect there are going to be some shared exposures in the way we process food – there are commonalities in the way human and dog foods are prepared and industrialised that are probably not good for our health.
I think there are chemicals that we use to prevent weeds and fertilise things that will probably turn out to be not very good for humans. I think microplastics in the environment, in our drinking water and in the oceans will turn out to be a really big problem and need to be eradicated. So I think there will be a lot of focus on real primary prevention, including smoking and those kinds of things. I suspect that in 2050, many of the bad things we’re doing now to our environment and to ourselves will just have been legislated out of possibility.
It’ll be interesting to see, because far fewer people smoke now than before, but the rates of bladder cancer are pretty similar. Now at the moment it’s probably because we’re a bit better at picking it up than in the past, but it will be interesting if in 20 years’ time we’re still seeing the same rates of bladder cancer with only a third of the rate of smoking.
How is it possible that we can sell a product like tobacco? Absolutely no health benefit and a known killer. That makes no sense, right? Like, come on.
Professor Inman, thank you for your time and all this fascinating insight.