Decoding the Immune Response in Early-Stage Bladder Cancer with Joshua Meeks, MD, PhD

Joshua Meeks, MD, PhD: We need to really start studying the immune cell part of this, not the tumor part. Because the tumor part, a lot of people have looked at; if the surgeon does a good job and gets rid of the tumor, that's less of an issue. But it's how the host or the patient works with the BCG therapy, that interaction, which is really trying to magnify the response of the host immune system, that's really what determines response to BCG therapy.

Erin Spain, MS: Today we're exploring new research into high-risk bladder cancer. Specifically, why a standard immunotherapy works remarkably well for some patients, but fails for others. Joining us is Dr. Joshua Meeks, the Edward M. Schafer, MD, PhD, Associate Professor of Urology, Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine. He's also a urologist at Northwestern Medicine. Dr. Meeks is a physician-scientist studying the biology of bladder cancer to help develop more targeted, personalized therapies. In this episode, we're going to talk about his recent findings on the tumor and immune factors that influence treatment response, and how those discoveries have the potential to transform clinical care. Dr. Meeks, welcome to Breakthroughs. 

Joshua Meeks, MD, PhD: Thanks for having me, Erin. I'm a big fan of the podcast, so it's super fun to be here and talk about it. 

Erin Spain, MS: We are so excited to have you here and talk about some of your latest research, but to give everybody a bigger picture of bladder cancer, can you tell me who is at the most risk for bladder cancer? How common is it and what makes high risk bladder cancer so challenging to treat? 

Joshua Meeks, MD, PhD: Yeah, it's really interesting when you get into some of the weeds on this cancer. It's actually very different as far as the incidence of men versus women. For men, it's the fourth most common cancer that they can get. It goes: prostate, lung, colon, bladder. So it's incredibly common. In women, it's much closer to around ninth most common cancer. So overall it kind of hits around sixth, but that gender disparity is real. Interestingly, we've seen that change and it's a changing dynamic. It previously was a cancer that got lumped in with smoking-related cancer. So you think about lung, you think about head and neck, and even pancreatic, and bladder was on there as well. At some point, roughly 60% of people who got bladder cancer were smokers. But that's really not what we see now. As smoking has largely gone away for most of our patients. And while other things have developed, smoking's gone down, the incidence of lung cancer has gone down. Bladder cancer, the incidence has stayed the same. So I think, there was something about it and it wasn't just carcinogen. Again, my theory is that it may be the inflammation driven by smoking. So today, when you ask me who the patient is with bladder cancer, I couldn't tell you. In fact, most of the patients that I talk to, we've seen basically a 1% increase in women and an increase in younger patients that are coming in with bladder cancer. It's not quite the extreme as what's seen in colorectal, but I'm definitely seeing a lot more younger patients. I would say the youngest I've seen some adolescents in high school, and then probably the average age is still in the 60s or 70s. But there is no sort of face of bladder cancer, and I really couldn't tell you the risk factors. That's part of what we do in our lab is try to understand what's causing this cancer. At a certain degree, I think it's a preventable cancer, but we just don't know the causes today. 

Erin Spain, MS: These gender disparities. What can you tell me about that? 

Joshua Meeks, MD, PhD: We studied that in our group. Andrew Houston is a grad student in my group that's really trying to study that. I did fellowship at Memorial and came back here on faculty in 2013. When I was here as a graduate student, we studied mouse models. So I said, let's start doing that here with bladder cancer. And there was really just one mouse model. You give the animals a carcinogen in their drinking water and they get bladder cancer. What's interesting is, when you give male and females this carcinogen, you get the same gender disparity. So there's something about that we don't really understand. Our leading theories are that it has something to do with inflammation. And again, it makes sense when you look at whether that be autoimmune disease, whether that be response to immunotherapy. Men and women have very different immune systems. Could that be hormone-driven? Certainly. But whether that's secondarily through inflammation, we don't know. But in women, it's a special group of patients. I actually have a fair number of patients that I care for at Northwestern that are women. We have the only women's bladder cancer support group in the world. They're very different as far as how they handle their bladder cancer, the way they think about it, it's very different than our men's population. So that support group is very good. But the biology of it seems different. The tumors are more basal. They tend to be overall a little more aggressive. There's certainly more of a delay when you look at the presenting incidence, it tends to be higher in women, and some of that can be just, they see their provider, they're given antibiotics for urinary tract infection, which they think is the cause, and it just keeps coming back and there's no infection. And ultimately that leads to an evaluation by a urologist. So there may be some delay, but we really don't think that's ultimately what's going on there. That certainly contributes to when it's picked up. But we think there's some biology that's different, and again, we're trying to figure that out. 

Erin Spain, MS: So your lab is really looking at this from multiple different angles. 

Joshua Meeks, MD, PhD: Again, we think that if you can figure out the gender disparity, then that lets you understand the cancer better. Obviously it's gonna lead you to better therapy in men versus women, but it's also a control, right? If you can figure out why men get this and why women get it at a different time point, and the women who get it, why do they get it? Is that because they're approaching menopause? It's something that we're just trying to understand better 'cause up until probably 10 years ago it was really just studied from a men-specific side. When we first started, we just did our studies in male mice because they got cancer more. We didn't start thinking about, why are women not getting this? Why are the female mice not getting this? And what's different about that? How does that contribute to our knowledge? I think that again, as a field, we're just trying to understand that better. 

Erin Spain, MS: Let's talk about some of the treatments that are out there right now. BCG has been the standard immunotherapy for high risk bladder cancer for decades. What is this treatment? How has it thought to work and what has historically made it so hard to predict who is going to benefit from it? 

Joshua Meeks, MD, PhD: Well, to answer the end part, we really don't know why it works. I think part of that problem comes back to the fact that you had urologists like myself studying it, that you're getting 80% there, so how is studying it gonna really help you? So it's interesting. If you look at the drug, it really was first used to treat mothers who were affected with pulmonary tuberculosis, and they were giving birth really at the turn of the 19th century. And so their children were immediately given this TB vaccine to prevent passage of tuberculosis. That way that it was produced is actually part of the formulary for how the drug is made and not changed. Why we give it is a sort of interesting story. It goes back to Lloyd Old. He was one of the first tumor immunologists in New York, and they found that you could actually inject BCG into melanoma and a lot of times it would go away. So then, the first study in humans was that a patient had a melanoma of a bladder, which is a very rare thing. When they injected it, it went away. So then the concept transferred over to thinking: Could you then put BCG into the bladder and would it have an effect? And sure enough, it did. And the response rates, as far as recurrence, went down about 50%. These are studies from the '70s, and really up until this year, we had our first FDA approval in June for a drug that beat BCG, and it was really adding durvalumab to BCG. It wasn't like it was replacing it, it was on top of it. So it's really incredibly effective. Why it works, ultimately, up until very recently, we had no idea. The concept was that BCG as an organism gets phagocytized by macrophages and by the epithelial cells, gets brought in, and gets exposed to the immune system. That brought a TB-specific immune response. But then shared among that was also the tumor antigens. So if you looked at patients that responded, they had both TB-specific responses as well as immune-specific responses. And so it was in many ways just bringing the immune system to the bladder and causing an immune response. That was sort of our best knowledge. We've tried to build off that a little bit with some of the work that we've done with Weiguo's group to try to understand that at the cell level. But really part of the reason we've not studied it as well is 'cause it works for probably three out of four patients. The challenge is that it's given once a week for six weeks, a minimum of 15 doses over a year. Over the last decade, we've been in a truly critical shortage of BCG. People anticipate that roughly half of patients who need it can't get it. So as effective as it is, there's just not enough of it to treat all the patients with bladder cancer. First of all, the cost to make this medication has not gotten cheaper because the way it's made is on these potato skins with bile acids basically on a flat surface at Merck. And the cost of this drug is incredibly cheap, but the need is very high. And you can't scale it up, it's not synthesized. As you know, with tuberculosis, it divides incredibly slow. You can't make that go faster without risking contamination. So one company now makes it for basically all of North America and Western Europe. 

Erin Spain, MS: So while BCG has been effective for decades, we still don't fully understand why some patients respond and others don't. Your team began by studying the tumors themselves. What did that research reveal? 

Joshua Meeks, MD, PhD: So this project went back to about over a decade ago when our guidelines said, if you're a high-risk tumor, the patient should really talk to the physician about having their bladder removed. And I was like, okay, so let's do the math. 87,000 patients a year are diagnosed, roughly a quarter of them could fit into this category. That's a lot of surgery for people that won't need it. And then there's a lot of people who may need it, and so they're not necessarily gonna get that offered to them. So is there a better test that we could develop to say, you have a tumor that we're worried about and has a high risk of progression? So it really was this biomarker that we said, if you had it, could help you. But the problem is there was no biomarker. There was nothing that we could say, we should really be studying this. We actually started here at Northwestern. We went through all of our patients and identified right around a hundred of them that we said, this is a cohort of patients that when they walk in the door, they could go either way. And so can we look at their tumors now that we have their outcomes and say, is there something about them that we could study or make a biomarker that we could implement? That was the first study that we did. It was published maybe five years ago in European Urology. And basically it was looking at all stage one cancer patients. And while there were some things, there was really no clear evidence from looking at the tumors themselves. We went back and added another 35 or 40 tumors. We added some DNA features to them, and that's when we really started looking at, okay, the tumors themselves were the same, but what was different about responders was they had a very much more inflamed microenvironment. So they were all a little different about what was causing them to be inflamed. Some of them, for example, had more immune cells, a lot of them had endogenous retrovirus signatures that were present, some of them had bacterial elements that you could find if you really looked at the metagenomics, so you could actually find bacterial DNA in the tumor. And so we said maybe that's part of it, right? If the tumor comes in inflamed, the patient may be more inflamed overall, and so they do better. That was really our sense that looking at, not just the tumor, but the host. That was over COVID and that's really where, if you look at what we learned from COVID, as a cancer surgeon, looking at my patients, you couldn't predict who would have a terrible outcome from COVID and those that would be fine and basically have a cold. The difference really came down to the patient and their immune system response. 

Erin Spain, MS: You mentioned inflammation, when comparing these responders and non-responders, tell me more about that and what key immune differences stood out. 

Joshua Meeks, MD, PhD: I think the biggest is that as these immune cells go into the bladder, you see a real increase in responders in a very specific kind of immune cell that's more of a CD4, TH1, like TH17 cell. And a lot of this work, obviously, we couldn't have done without our collaborator, Ryan Brown, in Weiguo's lab. He's a T-cell biologist, and we try and pull him into as many bladder projects as we can. That's really what's driving the response. And it's not surprising because, if you go back to the tuberculosis literature, and BCG is not an active form of tuberculosis; it's got parts of the genetic code that are missing, which makes it a very reasonable vaccine. If you look at the tuberculosis response and those who get this latent tuberculosis, those patients in general have less of a TH17 response. And so that sets up this phase where the tuberculosis can hang out in the alveolar macrophages. And again, that suggests it's this interaction of the macrophages and T-cells where you're getting that interaction. And we saw that in the bladders, right? So it's affecting the CD4 response, and that's primarily through the communication, again, that cell chat, that communication between macrophages and T-cells where you're getting macrophages causing suppression in non-responders or macrophages causing an increase in IL-17, IL-26, those are being driven by activated macrophages in responders. That divergence of the communication between the myeloid population, the T-cell population, that's really what's driving the response as far as what we see in our patients. 

Erin Spain, MS: Your more recent study, published in the Journal of Clinical Investigation, takes this a step further by examining the patient's immune response rather than just the tumor. How did you approach that research differently? 

Joshua Meeks, MD, PhD: What we saw in the lab as we were looking at the RNA from the responders, we were saying, wow, inflammation in the immune system seems to really be playing a role, like the host, the patient getting the therapy, really seems to have more of an impact than the tumor itself. It let us start asking questions about the host immune response. And innovation, which this university sees a lot of, really comes from bringing in new techniques. The question itself clinically was not that interesting. It was really saying, okay, when a patient shows up with a tumor, if you look before and after BCG, is there something different about the responders and non-responders? It's a very simple question. There's nothing about it that's incredibly new. But we found what was new here was, number one, we used single-cell sequencing technology to really be able to try and preserve the myeloid populations. So, that technology was a little bit innovative and that no one had really done that before. But the second is that we said, we don't really wanna sample the tumor. What we wanna do is move adjacent to the tumor and get pieces of normal urothelium. So we looked at the tissue microenvironment next to the tumor because we didn't really wanna look at the tumor. People have done that. That's already been studied. We wanna say, okay, for this patient, what's going on in their bladder microenvironment? And so that's how we set up the study is looking at that and then we compare that to blood from the patients, which we got at the same time. So we're thinking about all the different places where there are immune cells, there's the circulating immune environment, and then those that come into the bladder. So we wanted to look at that evolution and say, if you look at those two compartments before and after BCG, is there anything we can learn about to predict who's gonna respond and who's not gonna respond? 

Erin Spain, MS: You talked about using single-cell RNA sequencing to examine the individual immune cells in these patients. And this was fairly unique in bladder cancer research. What made you decide to go that route and use this technology to really see what you couldn't see before? 

Joshua Meeks, MD, PhD: I think the biggest reason that we got interested, some of it is some of our prior research looking at inflammation, which kind of pointed to that. So we do a procedure called a flexible cystoscopy. It's a small camera that we'll insert in the bladder. But what I found amazing was that when I would do cystoscopies, and when you give someone BCG, their bladders become almost like a snow globe, like they have so many immune cells that come in. We call it pyuria, but really it's immune cells that come into the bladder, and the bladder gets very red and inflamed. All of that is inflammation. Some patients you give the same therapy to, they have no response. Their bladders are pale. They have no immune cells at all, and so what was kind of amazing is thinking like, well, if I'm observing that in patients who are getting BCG who respond well, is that what else is going on at the tissue level? And so we need to really start studying the immune cell part of this, not the tumor part. Because the tumor part, a lot of people have looked at; if the surgeon does a good job and gets rid of the tumor, that's less of an issue. But it's how the host or the patient works with the BCG therapy, that interaction, which is really trying to magnify the response of the host immune system, that's really what determines response to BCG therapy. 

Erin Spain, MS: So taking all this together, the tumor biology, the immune profiling, this has given you a much fuller picture of what's going on with these patients. How could this combined approach eventually help identify who's most likely to benefit from BCG and who may need alternative treatments? 

Joshua Meeks, MD, PhD: So you'd love to know that when people walk in the door, are they someone whose immune system is already a little quiet and you'd kinda like to push that up? Or alternatively, one possibility is that people are already inflamed and they need less, right? So you can de-intensify some of those patients. And it may not be as simple as inflamed or not, but there are ways to drive that up. And so some of it is, you'd love to look at biomarker testing to get a sense about that in some ways, whether that be urine or tissue. One thing that we're very interested in is that the gut microbiome is really working along with a lot of this. So, we have a clinical trial here that we've developed where you could add a probiotic to be given with BCG for patients and see, does that help? If you have butyrate-producing species, can that help drive more TH17 response and affect the response to BCG? So that's a way where we're gonna try and do that to see if we can improve the response. But you would love to know at the precision level, how are patients likely to respond and do they need more, or perhaps the surgery we do to get rid of the tumors is all people need, maybe they need less BCG, maybe they need nothing, or maybe they need six doses. That's kind of how we're trying to apply that directly to our patients, and we'll be testing that in our trials that come up soon. 

Erin Spain, MS: What are the next steps now? 

Joshua Meeks, MD, PhD: What we've talked a lot about is the immune response. The part that our lab has been very interested in is using urinary tumor DNA to really get a snapshot of what's going on with the tumor. Because when we look at patients, no matter what their bladder looks like, we're going to give them medication in their bladder. That's, again, guideline-directed therapy. If you have a high-risk tumor, you're gonna get a year of therapy as long as you can tolerate it. But that means everybody gets the same. And it's interesting, you give people medication and maybe three or four doses in, people have to stop because their symptoms are so bad. So they're done. They've gotten all they need. Other people have no symptoms at all. Again, we think a lot of that relates to the toxicity of therapy. So you'd love to know that ahead of time. So the trials we're doing are, number one, look at who's got urinary tumor DNA that shows up ahead of time, and so they have at the microscopic level some tumor, so they may need more. Who's clear of that? And can we back off and de-intensify those patients and maybe give them less? And then the question is, how do you turn that up? You intensify. There's different therapies we can give like checkpoint inhibitors, but again, we're very interested in probiotics to alter the gut microbiome. There's good data from checkpoint therapies that you can do that. So can we do that in bladder cancer in early stage, it's tolerable and can improve the response? 

Erin Spain, MS: Does this point to things that we should be thinking about to prevent bladder cancer? Like you mentioned, the gut microbiome, diet, what we're putting into our bodies. Is this something that we should be thinking about as far as prevention? 

Joshua Meeks, MD, PhD: The problem that we have is that to a certain degree, with this information, it's all pretty unique to the patient. That's where we've gotten into multi-omics and tried to understand this better at population scale. But we're trying to study that in our lab, right. In controlled environments where you have mice, you give them antibiotics to clear their gut, there's pretty good data that if you can change that around, you can decrease some of that inflammation. We'd love to try and do that to see if there's more holistic ways of trying to figure out why they got their cancer and can we change that? That's almost what we have to do at this point. Because if you look at what exposures are, especially when you look at people who are not smokers, they have no risk factors, they're not working with chemicals, so how do they get this cancer? What is the thing we're chronically exposed to?  

Erin Spain, MS: And that is part of the point here is precision medicine. We're trying to find this individual, what's going to work for them.  You've come a long way, even in the past decade. Talk to me about the goals for the future. You've mentioned clinical trials, gender disparities. Eventually, where would you like to see your lab going like 10 years from now? 

Joshua Meeks, MD, PhD: We've really focused on early stage bladder cancer here. But I'll tell you, for the more aggressive cancers, we have new therapies that have completely changed how we treat patients with stage two, stage four bladder cancer. We think our mortalities are gonna go down significantly. The rates of doing radical surgery have gone down amazing as far as we're not really needing to do that 'cause the therapies are so good. So a lot of patients were shifting from lethal metastatic bladder cancer to these early stage tumors. Now, I think from our group, what we'd love to understand is, how do we best align therapy with patient and then how do we best know how to treat them where we're able to decrease some of the toxicities of that. I think that's what's at this point, probably limiting much of our both systemic as well as early stage therapies is that we have drugs that work, but they still cause toxicity, and that can affect patients' quality of life and their ability to stay on therapy. So how do we identify those earlier? How do we basically dose those where they're not gonna have toxicity for our patients? I think that's really where our group would love to go in the future, is picking better therapies for our patients and really being able to say, this is the best what you need and we can back off on the rest. 

Erin Spain, MS: You mentioned your collaborators. Why is this something that could really only happen at Northwestern? 

Joshua Meeks, MD, PhD: It's really an amazing campus. I've been a Northwestern homer now since 1998. I was thinking back, so that's a long time. But what's kept me here is the fact that we're a very horizontal group in that everyone collaborates together in a very small space. So my research group is built within biochemistry. I'm a urologist. My department is urology, but I physically live in biochemistry with Alicia Latford. So my space, my collaborators on a day-to-day basis are my biochemistry colleagues. And they're seeing things from a basic science side that I see from a clinical side, and where we find harmony is working together. Weiguo is another example of that where he's in the Department of Pathology. Again, we have all these groups that work together and commonly are working together because we're not on different campuses, we're not across town. We're just in a few buildings, and for me, the reason this project was able to be successful is I was able to bring samples from our patients from the operating room directly over to the lab, and that walk is probably under a minute and a half. Those are fresh samples that can be processed immediately. And again, I think that led to being able to study these myeloid populations like neutrophils. Which have been extremely hard to study before. And they maintain their form because they're not in a van going to a different part of the city. It's just a few-minute walk and we can get them right into fresh culture and study them. 

Erin Spain, MS: What an incredible example though of how proximity and this greater plan that Northwestern Medicine has to bring the physician-scientists, the labs, to bring these folks together. I think it's a really cool illustration of that. As we wrap up today, what do you want listeners to know about bladder cancer today and the future of bladder cancer from your perspective? 

Joshua Meeks, MD, PhD:  Yeah, again, I think it's a cancer that most people have probably not heard as much about. We lend and borrow a lot from our colleagues and other solid tumors, from melanoma, from lung cancer. But there's a lot that you can learn about from that, and it's an amazing time for our patients if any of them are listening. There's so much going on from an innovation perspective. There's patients that, unfortunately, I lost early in my career where we just didn't have therapies. We saw immunotherapy come around and many more people live. We now have ADCs that have changed that. So it's just an amazing time to be an investigator, but also to be a provider. And again, I think a lot of our work comes from collaboration amongst people at our own institution. So it's great to be at Northwestern. 

Erin Spain, MS: Thank you so much, Dr. Joshua Meeks for coming on the show today. 

Joshua Meeks, MD, PhD: Thank you for having me, Erin. 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

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Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

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American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Joshua Meeks, MD, PhD, has received honoraria from Olympus, CG Oncology, Immunity Bio, Photocure, Protera, Imvax, AstraZeneca, astellas, Pfizer, Inc., Prokarium, Axiom, Platform Q, Johnson & Johnson, Bristol-Myers Squibb, Urogen, AUA, Merck and Company, Inc., and Ferring. Meeks has ownership in meshsuture. He has also received grant and research support from Merck and Company, Inc. and Epizyme. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and staff have no relevant financial relationships with ineligible companies to disclose.