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“There’s a new vitality in bladder cancer. And it’s exciting to have come through 20 years of agony and start to see the fruits of all that labour”

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"The new vitality in bladder cancer" – the June 2022 Combat Medical Innovators Interview with Professor Michael O'Donnell, Director of Urologic Oncology & Richard D Williams Professor of Urologic Oncology at the University of Iowa

The Medical Innovators Interview with Professor Michael O’Donnell | June 2022

Gem/doce vs BCG, quantum dots and the future of uro-oncology come under the microscope in our June Medical Innovators Interview, with Combat Medical’s Guy Cooper in conversation with Professor Michael O’Donnell, the pioneer of combination intravesical chemotherapy (including Adriamycin, gemcitabine, docetaxel and mitomycin) in non-muscle-invasive bladder cancer for patients in whom first-line BCG has failed.

Professor O’Donnell is the Director of Urologic Oncology and the Richard D Williams Professor of Urologic Oncology at the University of Iowa. After gaining his medical degree from Duke University, he was a resident in urology, a clinical and research fellow, and assistant professor in surgery at Harvard. He also undertook a biomedical research fellowship at the Whitehead Institute and Beth Israel Deaconess Medical Center in Boston. The author of more than 100 peer-reviewed manuscripts, 10 book chapters and multiple reviews and abstracts, he is an editorial board member of the Journal of Urology and CURE, leads several national immunotherapy clinical trials and holds US patents in the genetic manipulation of BCG bacteria.

Professor O’Donnell, it was a pleasure to hear you speak about gem/doce and other interesting bladder cancer topics at the AUA Annual Meeting in May, where I think one of your colleagues referred to you as the mad professor of mixing things up in oncology…

No, it was the mad scientist of urology…

Mad scientist – there we go.

…which I took as a very personal compliment.

So let’s talk about some of these mad science things – although I’m an orthopaedic surgeon by training, so if you could keep the words short and the concepts relatively simple, I won’t bleed from my ears. I’ll probably say something horrible about urologists on the way through, but you’re more than welcome to punch back.

I don’t expect any more from a bonehead, so it’s OK.

You have all the same jokes over there that we have here! So how did you get to where you are now?

For about 20 years I’ve been working on developing combination chemotherapy intravesically for bladder cancer. When I started out, it struck me as unusual that in medical oncology you practically couldn’t find any single-agent therapies for systemic disease, whereas in urology we had limited ourselves to simple drugs to put in the bladder, such as Adriamycin, mitomycin, thiotepa and so forth. And the results were better than placebo but quite substandard, especially when compared to a relatively unusual biological treatment, which was BCG. And I wondered why we couldn’t use more than one drug in the bladder.

Now it just so happened at the time that all the drugs available were so-called vesicant drugs – the types that, if they extravasated from a systemic therapy infusion, would cause significant tissue necrosis. That’s how vesicants established their names – they would cause terrible tissue reactions, necrosis and so on. And it struck me that perhaps there was no successful use of combination bladder-cancer therapies because the dose-limiting toxicity was actually chemical cystitis. I was able to dig up an intrepid Japanese urologist, who’d come up with a successful treatment of same-day Adriamycin and mitomycin, used it for carcinoma in situ and was getting 75- 80% complete response rates, but fully three-quarters of the patients had debilitating cystitis. That was a problem.

Then as new agents such as gemcitabine, docetaxel and others became available, we started to move into the possibility of non-vesicant drugs, so the first thing I tried was combining a single-day treatment of two drugs, one right after the other, gemcitabine and mitomycin. This was for patients where BCG had failed, where conventional single-agent therapy was relatively poor and where we were looking at 20% one-year disease-free rates. We actually got a very reasonable response – a one-year disease-free rate of 50%-plus. And at two years, it was 35%. And we had only the typical effects of mitomycin – the hand/palm rashes, the bladder irritability, stone formation, things like that. So it wasn’t any worse than mitomycin and it looked like it was a better regimen.

And then, like many drugs in this current century, mitomycin went into shortage.

At the time, Jim McKiernan at Columbia was just publishing his work on single-agent docetaxel on the bladder – very low toxicity but a signal almost equal to gem/mito. So I switched from gem/mito to gem/doce.

First of all, we noticed there was almost no drug toxicity, both agents being non-vesicant drugs. And secondly, we got very high levels of response – 60-70% complete response rates, even in the very refractory BCG-unresponsive CIS cases. And our durability was much greater, too. We were still seeing levels of durability in 35% of patients three years later.

Long story short, we then started to expand our indications to papillary disease, to early failures after BCG, maybe after one cycle, to upper tract disease, and even eventually used it on a few patients who couldn’t get BCG as first-line therapy. And our results were nothing short of remarkable. Patients had minimal toxicity, yet they had extraordinary responses. I was sharing this data with different investigators at meetings and they were enthusiastic about taking my protocol and trying it at their institutions.

With gem/doce, there was almost no drug toxicity and very high levels of response – 60-70% complete response rates, even in the very refractory BCG-unresponsive CIS cases. And durability was much greater, too. We were still seeing levels of durability in 35% of patients three years later

We were able to put in a 11-group retrospective database, which was published in May 2020 in the Journal of Urology (Steinberg et al), where we found that among all the BCG failures, over 50% were cancer-free at two years. And among the technically BCG-unresponsive CIS population, it was exactly 50%. For the papillary patients, it was 58%. Then the BCG shortage hit in 2019, and I knew we would not have enough BCG to treat all the patients who were at my institution or being referred to us. At that point, I had unilaterally treated 35 patients with gem/doce upfront instead of with BCG and, remarkably, the two-year disease-free rate was close to 90%.

So I switched everyone. Practically every new patient who came in got upfront gem/doce instead of BCG. And we’ve just reported our results at the 2022 AUA meeting, with 107 patients with high-grade, non-muscle-invasive bladder cancer, about 40% with CIS and another 40% with T1 disease – the real heavy-hitter type diseases. And our results at two years were 84% freedom from high-grade disease and 82% for any recurrence. We only have one patient with a Ta low-grade recurrence.

I’m getting close to 10 years now of travelling around the world. The US’s drug choice for bladder cancer has always been slightly different, but it’s been equally singular in that, historically, you’ve just used one drug. And everywhere else I go in the world, everybody uses mito. And I could never quite work out why. I ask the surgeons, “Why do you use mitomycin?” and they reply, “Well, we’ve always used mitomycin.” And you’ll find some places where they use epirubicin, but only because they can’t get mitomycin. And we also work also in the world of HIPEC, which is exactly the same concept of heated chemotherapy for additional absorption as HIVEC. But with the medical oncologists for abdominal and peritoneal surgery, it’s like they’re Michelin-starred chefs. Everybody has their own chemo mix. There’s a pharmacopoeia of things being used. And then we come to the urologists, and everybody in the world uses what they’ve always used because it’s what they’ve always used. Why do you think that is?

I think people are creatures of comfort. They like to have a programme that works for them, that they’ve got a workflow for that works in their office, that everyone is familiar with, even though mitomycin is probably the worst drug you’d want to have your nurses fooling around with. You get that stuff on your skin and you’re going to get a blistering scab.

In some places I go to, they have to have a fume cabinet and a writ from the Pope to mix it. But in others they mix it at the bedside. That has always amazed me.

And this is what amazed me when I started to talk about these two new drugs – gemcitabine and docetaxel – which you could practically bathe in without any trouble. And some of the biggest apprehension came from the nursing side: “How can we deal with this kind of chemotherapy?” I didn’t want to tell them, “Well, you’re working currently with the equivalent of a nuclear bomb, and here’s something that’s a firecracker by comparison.

Well, I’ll come in from a slightly oblique angle. What little bit of urology I did 100 years ago at the Whittington Hospital in London involved BCG and mitomycin, and that was it. And 20 years later, it’s the same. But if you wander around AUA, as we did a couple of weeks ago, there are a thousand new innovations. If you come forward one organ to the prostate, in my youth you were given a monopolar loop and told to get on with it. But there’s now every form of energy, knot, tie and stent, and some barbaric nitinol cutty thing, yet we go back an organ to the bladder, and everybody still does the same as they’ve always done.

Exactly.

The urologists seem quite innovative in some ways but enormously conservative in others.

They’re innovative when it comes to toys. When it comes to lasers, ultrasonics, robots and microwave, they love the idea of playing with a new instrument. However, they are reserved with chemotherapy because they haven’t been trained as medical oncologists. And that’s why pembrolizumab has been only reluctantly used by urologists in the United States, because they’re afraid of it. They don’t understand immune adverse events but they’ve heard of people dying from them, and that is enough to keep them away from it.

Pembrolizumab has been only reluctantly used by urologists in the US, because they’re afraid of it. They don’t understand immune adverse events but they’ve heard of people dying from them, and that is enough to keep them away from it

And it seems a shame, because from what was regarded – with the greatest of respect – as a very solid but workaday specialty in the 1990s when I qualified, the urologists have become the rock stars, with all of the toys, including the robot, which you can talk to anybody about in the saloon bar. Everyone’s heard of the robot. But I don’t think many people realise it has become a tool for prostatectomies and radical cystectomies. I remember seeing some valve replacements being done with it about 15 years ago, and we thought it would be the tool of cardiologists and the neurosurgeons, but you guys have stolen the march. Is it the difference between devices and drugs? That urologists are quite happy to be innovative with devices because then it’s still in your own hands, but if it’s a drug, it moves into other people’s areas?

I think that’s exactly the reason. You’ve hit the nail on the head.

It’s a strange one. Even BCG always seemed a fairly orthopaedic response to the problem – let’s give a part of the body this terrible disease that the body will then attack, and it might coincidentally cure a secondary disease you already have. It’s a fairly blunt instrument.

It was, and it still is. And, even 40 years later, we still don’t precisely know how it works because everything you look at that involves the immune system is activated by BCG. And maybe that’s precisely why it works, because it turns everything on. It’s like throwing a hornets’ nest into the bladder.

I can’t discuss immunology too much without bleeding from my ears, but that’s how I see it in my simple, linear brain – that you’ve caused a massive immune response. And it’s a little bit strange that more drugs haven’t been mixed, because the abdominal surgeons use all sorts of stuff, and they have to put up with a much greater systemic toxicity because they’re lavaging your abdomen for 90 minutes with it. Nature has been very kind to the urologist and provided a small, waterproof bag, largely with only one way in and out. I would have thought this was a prime opportunity to mix up some different potions.

You know, it really is. You can put practically anything in the bladder. Put in diluted bleach, call it a different name – Clorpactin – and suddenly you have a treatment for another weird disease, which is interstitial cystitis. The bladder is such an impermeable organ and the tumours come back so frequently that you actually have multiple chances at it.  

How do you see this playing out? I won’t take you too far into the future because I’ve got some further questions about that, but BCG failure is still a big problem. Bladder cancer is a disease state that the FDA has highlighted as one of the things it will fast-track almost any effective procedure for. And by effective, I mean 30% recurrence-free at six months, which doesn’t sound massively effective to somebody used to doing arthroplasties. Where are we going next? What’s going to be the next thing?

Well, for better or worse, no therapy is perfect. There will always be failures. What that practically means is that there’s room on the table for all kinds of different ideas. It’s just a matter of when do you pull the plug. We used to take out bladders when the second course of BCG failed. And it wasn’t because that patient was imminently about to develop metastatic disease, but because we had nothing better to offer them. At that point, the chemotherapies were, at best, 20% effective. Yet interestingly, the FDA recently approved pembrolizumab for a one-year disease-free rate of under 20%. Likewise, valrubicin is 8% at two years. We haven’t really moved far with the approved medications.

We’re now seeing several people coming through with proposals where the one year disease-free is 20-25%, maybe up to 30%. There has been some new exciting work from the combination immunotherapists using the IL-15 superagonist with BCG and getting results that are actually very similar to what we got with gem/doce – 70% complete response, 60% at one year, 50% at two years. And hyperthermic mitomycin therapies are in the same ballpark. It’s going to come down to what is affordable. Pembrolizumab is $10,000 a treatment.

So if I give you a billion dollars of research money today for one line of investigation and one big trial, what are you going to spend it on?

I would have a prospective randomised trial with several alternatives. Let’s take the top three – N8O3 + BCG, hyperthermic mitomycin and gem/doce. And I think we’ll find they’re all pretty much the same but with different toxicity profiles. And then I would add to that the ability to do crossover, because we want to save as many people as possible, using the correct sequence of complementary treatments to achieve something over 90% for the whole population.

Well, we are talking about trying to find one technology that can go forward to treat BCG-unresponsive or refractory bladder disease. But in everything else that you do, such as with prostates, you’ve got 10 different things to use. Why not try all of them with bladder cancer? And from talking to some of your colleagues, this is exactly what they’re saying – that we need in our armamentarium two or three things to either try as golden bullets or as sequential treatments, because somebody’s tumours or somebody’s urothelium or somebody’s something just will not respond to gemcitabine.

Well, the second thing that that $1 billion would be invested in would be complex genomics that would identify fingerprint patterns to increase the likelihood that one treatment would be better in a particular subset group than another.

Urinary biomarkers for tumours would be a great step forward for bladder-cancer treatments, and then proper genetically sequenced, analysed biomarkers that show if you’ve got the sort of tumour we know is particularly susceptible to nadofaragene or gem/doce or something else.

Yeah, exactly.

How far are we away from that, then? There’s been nothing but mitomycin and BCG for the last 40 years. How long is it going to be till we get there?

In times of crisis, compromises and changes are forced upon us. I wouldn’t have gotten this far with gem/doce, and certainly not in the upfront setting, had there not been a global BCG shortage. And now we have a rival to BCG as upfront therapy, which threatens to change the whole game. So now we’ll be looking at how good BCG is as a second-line therapy or if hyperthermic mitomycin would be the next best thing to use. Where does BCG fit in to this? Is there a particular pattern of relapse that suggests a completely different mechanistic approach, that going to immunotherapy would be better than going through chemotherapy? I mean, there are probably a limited number of resistance pathways that can be mapped out.

Now we have a rival to BCG as upfront therapy, which threatens to change the whole game. So we’ll be looking at how good BCG is as a second-line therapy or if hyperthermic mitomycin would be the next best thing to use

But if we could map them, it would give us a much stronger route through, wouldn’t it? When our friends at Sanofi stopped manufacturing BCG, the reasons were that they had a flood and then it was too much work and money to turn it all back on properly again.

And they weren’t making much money. I mean, for a drug that is as effective as BCG, it’s substantially underpriced.

We know the guys from Medac, the German pharmaceutical company that makes excellent versions of mitomycin and BCG, and they say the same. Twenty years ago, we thought tuberculosis was a disease of the Victorian era that we could write off along with smallpox and scrofula, but nature finds a way. In the UK, it’s about £100 for a TB vaccine and about £100 for 40ml to put in the bladder. And from a full SWOG protocol of BCG for one patient, they can make something like 10,000 vaccine doses. I’m no accountant, but I can see where that one’s going.

Yeah. It’s like learning from history. You have to know what has come before and how it has set the market and the stage for everybody else. And then you have to decide, well, are you going to throw away the old workhorses or are you going to remodel them?

There are a couple of new players and BCG strains licensed in extremis, but we are just trying to repatch the same hole in the boat. The time has come to move to a different, not single, therapy, but a raft of therapies that will give you as many options for bladder tumours as you’ve got for BPH and other treatments.

I totally agree.

OK. We’ll look at it slightly differently, then. I have in my garage, here in Yorkshire, the DeLorean from Back to the Future. I’ll throw you the keys…

I’ll tell you what. I’ll race you with the Tesla.

… and you whizz forward into your oncology clinic in 40 years’ time. What does it look like?

Well, the goal of every surgeon should be to make surgery obsolete. I think we’re going to have some form of smart nanotechnology you put in the bladder, which has particular sensors for certain protein signatures that target a small, little ionic blast and wipe out the cell. And it’s so specific because it requires three different triggers that must all be present at the same time. You may throw in a little bit of something else for overall coverage, but your money is going to go with this extremely precise smart-bomb approach.

You’re not the first to say this. I don’t know of any companies working on this now, but I’ll bet they’re out there.  

My daughter is an engineer, and she was telling me that they’ve got these little things that can crawl around and send little homing signals, so it’s already here in its infancy. It’s just a matter of applied engineering.

How do we get there? Are we getting there through gem/doce or some other immunotherapy?  

I think you first need something that works, and then you’ve got to go incrementally beyond that and start to invent new therapies to fill the gap. Then as those therapies become more effective, they’ll basically wipe out the old ones.

And we are hoping to start seeing a little bit of that now. We say there’s no innovation, but we’ve seen the pembrolizumabs and the PD-L1s, the nadofaragenes, the immunologic stuff and some of the more replicable things from other surgeries or specialties – so it’s not just about using the same drug all the time and expecting to get different results.

Right. We have that much. Nor can we take two ineffective drugs and expect them to be more effective just because of how they’re mixed and matched one week versus the next. And that’s a lot of what happened with the Europeans’ attempts to combine immunotherapy with chemotherapy. We’re basically just alternating week by week or three weeks in a row with one, three weeks in a row with another, and I would say that’s relatively naïve.

We have a two-year study from Leicester University in the UK. Leicester is not particularly famous for anything, although they won the football Premier League a few years ago at 5000-1 odds, much to everybody’s amazement, probably not least their own. But they do have a large university there and a very large urology department with good results on a sequential bladder cancer therapy, based on “we’ve only got three doses of BCG per patient, so that’s all we’re going to use, and we’ll fill the gaps with something else”. And we don’t know why the headline results look good – we don’t know if the immunotherapy boosts the chemotherapy or vice versa, or if it just gives us twice the drug to go for two different sorts of patients, one of whom would be appropriate for chemo and one for immunotherapy.

Right. It’s like throwing a bigger bomb, or two bombs – incendiary and something nuclear.

Something even worse. Is there anything else you think is interesting and innovative that we haven’t yet covered?

I think that would cover most of it. There’s a lot of talk about coming up with an MRI-based, better method of evaluating bladder tumours and so forth. Sort of the PI-RADS for bladder. I forget what they call it. The VI-RADS? But I’m not really too impressed by that. I think even such things as photodynamic therapy will make a return as we begin to understand the physics of effective energy transfer, and we can now have more efficient targeting. The whole fact that immunobiologicals are being created that allow a specific targeting is, I think, going to be a big deal. But I believe we’ve only scratched the surface on that one. I wouldn’t be surprised to see something like quantum dots, that are highly efficient at transferring energy, being coupled with very specific antibody or aptamer-related targeting proteins or nucleic acids to get a more focused concentration of energy effects to create a very specific photodynamic therapy.

The ablation of the tumours or the surgical removal of the tumours is as undeveloped as the treatment thereafter…

It’s barbaric. I mean, it is medieval, some of the stuff.

Well, what little bit I did in probably quite a medieval fashion 30 years ago is still the treatment.

It’s kind of like orthopaedic surgery, for God’s sake.

I joked about the prostates and monopolar loop, but that’s still pretty much where the bladder tumour is. And we know from our work in abdominal peritoneal spread and the pseudomyxomas that the biggest prognostic indicator is the surgery and how close you can get to T0. There’s a lot of space in the abdomen and you’re always losing something or not seeing something because it can’t be seen. But I wonder if we could not only do what we assume to be a very good TURB either by eye or narrow-band or blue light, but if we could also do it with an energy that is much more ablative and focused. That would probably be another big move. It’s funny – it’s such a common disease, yet so little has been done for it in 30 years.

I know, it’s terrible.

Although it does mean there’s a great opportunity for innovation in front of us.

Well, you know what happened? Bladder cancer is coming into the spotlight and we have to thank the FDA for that because they basically created a low-hanging fruit – with a trial of 100 patients, you can get your drug approved and make millions of dollars. So now suddenly there are a lot of players in the game. It has created this energised interest in bladder cancer and now we’re attracting young, energetic, interesting people who grew up in the gaming environment and understand that the rules are what you make them. I think that’s going to be the new vitality in bladder cancer. We’re on the cusp of it right now, almost in the middle of it. And it’s exciting and very thrilling to have come through 20 years of agony and finally start to see some of the fruits of all that labour.

Bladder cancer is coming into the spotlight. Suddenly there are a lot of players in the game, and I think that’s going to be the new vitality in bladder cancer

Wonderful. I didn’t think we would finish the interview by thanking the FDA. It normally doesn’t go that way, but we’ll take that as an innovation as well! Thank you very much for your time. It’s very interesting to see that not everybody is doing what they’ve always done but that there are some innovative intellects out there looking to do the next big thing for bladder cancer.

Yeah, that’s where the fun is.

Our aim with these interviews is to put some interesting ideas out there about how we should be treating bladder cancer, to hopefully help keep it as something people talk about, and maybe move it along.

I totally love it. Thank you for involving me.

If you’d like to share your own ideas and opinions as a fellow medical innovator, please email Guy Cooper at
grc@combat-medical.com

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