Selected Podcast
Predicting Which Bladder Cancer Patients Will Respond to Immunotherapy
Northwestern Medicine scientists, led by Joshua J. Meeks, MD, PhD, have developed a biomarker signature test to predict which patients with bladder cancer will respond to immunotherapy. The discovery, from a new study published in Nature Communications, could improve the survival of bladder cancer patients. Dr. Meeks joins this episode of the Better Edge podcast to discuss the results.
Featured Speaker:
His research laboratory is focused on the molecular pathways involved in the progression of urothelial carcinoma (bladder cancer). His research has two themes: 1) to investigate the epigenetic mechanisms of gene regulation in bladder cancer and 2) to identify the interaction of the immune response to tumor mutations.
Joshua J. Meeks, MD, PhD
Dr. Meeks is an Urologic Oncologist and Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, He is a urologic surgeon with expertise in the diagnosis, treatment and management of bladder cancer. His research interests focus on both the epigenetics and genetic mutations associated with cancer biology. Specifically, he is studying how chromatin remodeling genes play a role in bladder cancer. In addition, he is investigating the “driver mutations found in bladder cancer. In the future, he hopes to develop novel systemic and intravesical therapies to improve survival of patients with bladder cancer.His research laboratory is focused on the molecular pathways involved in the progression of urothelial carcinoma (bladder cancer). His research has two themes: 1) to investigate the epigenetic mechanisms of gene regulation in bladder cancer and 2) to identify the interaction of the immune response to tumor mutations.
Transcription:
Predicting Which Bladder Cancer Patients Will Respond to Immunotherapy
Melanie Cole, MS (Host): Northwestern Medicine scientists led by Dr. Joshua Meeks have developed a biomarker signature test to predict which patients with bladder cancer will respond to immunotherapy. The discovery from a new study published in Nature Communications could improve the survival of bladder cancer patients.
Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And my guest, Dr. Joshua Meeks, is the Edward M. Schaeffer Professor of Urology, Associate Professor of Urology, Biochemistry and Molecular Genetics at Northwestern Medicine. He's a urologic surgeon with expertise in the diagnosis, treatment and management of bladder cancer.
Dr. Meeks, it's a pleasure to have you join us today. I'd like you to start by telling us why has checkpoint immunotherapy historically been more difficult to use to treat bladder cancer? What is checkpoint immunotherapy and why are biomarkers of response to immunotherapy needed?
Joshua J. Meeks, MD: Hi. Great to talk, Melanie. Thanks for having me on. This question really kind of comes from a real sticking point with how we take care of our patients at Northwestern and across the world really. This bladder cancer is a very aggressive cancer and, in general, around 17,000 to 18,000 patients in the US are going to die from bladder cancer. We tend to think that, while surgery has one part, trying to care for patients with cancer that leaves their bladder and spreads to the rest of their body is really where the fight's going to be won or lost. And up until the early 2000s, the Nobel Prize for the immunotherapy was awarded in 2018. So, that gives you a sense that really this is a new revolution of therapies. And the whole premise of this is that as these cancers develop, they're sort of waging a war with your immune system, and they're smart enough where they're able to turn off the features of the immune system so that the immune system kind of goes to sleep and doesn't recognize a cancer as being foreign. It thinks it's part of the host of the body. The drugs work by turning off these off signals. So, it's a double negative. It actually turns on the immune system to recognize the cancer and come after it. And so, these therapies, you know, again, I've got loads of patients who are alive who have prolonged survival just because they happen to be alive when these therapies come around. The problem though is that most responses are not durable and, long term, the response rate is around 20-30%. You get an initial stabilization. But realistically, only one in three patients will have a long response to immunotherapy. And the challenge is, number one, trying to identify that third. And the other part is, are there better therapies we should be using to add to immunotherapy to let them work better?
Melanie Cole, MS (Host): Thank you so much, Dr. Meeks. Do any biomarkers exist as of now that can help guide treatment decisions about immunotherapy? Tell us about your published research in Nature Communications that describes this biomarker signature test to predict which tumors will respond to immunotherapy. Tell us about the study and how your team identified this biomarker.
Joshua J. Meeks, MD: So, that's kind of what we ask with study. So, all of this work really was a multi-institutional and a multinational collaboration. So, we started working with a group out of Milan, Italy. The investigator's name was Andrea Necchi. He had the first real trial in bladder cancer where a patient comes in with a tumor, and then you give the patient a therapy called pembrolizumab, which is a form of immunotherapy. And then, the patient has surgery to have their bladder removed. And so, that lets you look at the tumor before treatment so you can get a bunch of analysis of that tumor, and then the patient gets treated. And then, you see did it work or not. And the key point is you can see when it didn't work, what were the resistance factors that were present. So, we started collaborating with him around 2018 or '19. They sent all the tumors from Italy to Northwestern. We did a full gene expression analysis on over a hundred patients and working with another scientist, his name is Gordon Robertson, who's in Vancouver. We sort of did a bioinformatic analysis to figure out could we identify not just who responded and who didn't, but mechanisms by which patients could or could not respond. And that really helped inform us to figure out, well, there's probably at least two ways that cancers are resistant and maybe three ways in which they respond and they're very different. And from that, we can start to figure out, again, next sets of therapies and really trying to piece this whole story together.
So again, we, were able to look at the tumors themselves. You know, we did little biopsies, extracted all the RNA. And then again, a lot of it is a lot of long kind of computational lifting to group the tumors together to sort of understand if you look at all the tumors that respond, did they look the same and no, they didn't. There's a couple different sets of pathways that show up. And I think what we can do with that and what we did was actually collaborate with another scientist, Clair Groeneveld, who is in Paris, to figure out could we set up a biomarker that we could look prospectively at tumors and say, if a patient shows up today, can we look at their tumor and say, "What are their chances of responding?" And that's really where we'd hoped this would go. We have patients every day making decisions about should they take immunotherapy or not. And honestly, it's a question of risk-benefit. Is the toxicity of the therapy going to be worth the potential benefit? And if you could tell someone, "I think you have a good chance of responding," then that risk is worth taking. Right now, it's a little bit of a blinded walk. And again, only 30% have a response and, otherwise, they're all just sort of risking toxicity. So, that's really where we're hoping to go with this.
Melanie Cole, MS (Host): Well then, other than optimizing treatment selection, Dr. Meeks, are there other potential benefits and/or downsides for bladder cancer patients that you work with them in that shared decision-making decision?
Joshua J. Meeks, MD: One of the more discovery parts of our study was that we could take some of those non-responding cancers. We were able to sort of identify a few pathways that were sort of aberrant. For example, one of them was a gene called FGF receptor 3. And there's drugs that target that. We don't have to think about just giving immunotherapy. You could say, "Well, we can combine therapies that target those vulnerabilities with immunotherapy." And there are trials out there that are going to start doing that. So, our hope would be to say, "Well, this therapy may not work completely, but what if we put a couple of these together to try to increase the robustness of the response?"
Melanie Cole, MS (Host): Well then, take us from bench to bedside, Dr. Meeks. How will your findings aid other physicians to determine which patients are likely to respond to immunotherapy? I'd like you to speak about how this will impact not only patient care and their journey down the line, but research down the line because it's absolutely fascinating.
Joshua J. Meeks, MD: Yeah. And I'd say where we're at with immunotherapy and bladder cancer is that there was a huge boon and a lot of these drugs received accelerated approvals. And then, gradually, a lot of that has receded away because we found that long-term the responses for many patients are just not durable. So, where we see this fitting in is that we think that if you take a hundred patients and only 30% respond, it's hard for those other 70 people that don't respond. But if you could identify those people ahead of time and say, "We have good precision to predict who will respond," then that really makes it a really viable option for them. So, what we're thinking is that where there is a possibility for immunotherapy, we could potentially use this test to potentially increase the response for patients.
Melanie Cole, MS (Host): I'd like you to wrap up for us by describing any clinical trials that will be starting at Northwestern Medicine within the next year, and your hopes for the future to develop novel therapies to improve survival of patients with bladder cancer. These are such exciting results and you're doing such amazing work. I'd like you to speak to other providers, Dr. Meeks, and tell them what you would like the key messages from this episode to be.
Joshua J. Meeks, MD: Yeah, I think the steps going forward is that we have a real luxury to have another form of therapy. The second wave of treatments for bladder cancer really involve these immunotherapies. But I think what we're finding is they're not a shotgun where we can apply them to everyone. They're going to be much more like a sharp shooting rifle where we have to know which patients will have the best response. And so, our hope is that we'll continue to be able to use these therapies, but provide them in the right manner. And hopefully, this work from our biomarker investigation can really try to identify those patients.
Melanie Cole, MS (Host): Thank you so much, Dr. Meeks. As always, you are such an excellent guest and so informative. Please join us again and give us updates as these and other clinical trials continue to proceed. So, thank you again. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/urology to get connected with one of our providers.
That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.
Predicting Which Bladder Cancer Patients Will Respond to Immunotherapy
Melanie Cole, MS (Host): Northwestern Medicine scientists led by Dr. Joshua Meeks have developed a biomarker signature test to predict which patients with bladder cancer will respond to immunotherapy. The discovery from a new study published in Nature Communications could improve the survival of bladder cancer patients.
Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And my guest, Dr. Joshua Meeks, is the Edward M. Schaeffer Professor of Urology, Associate Professor of Urology, Biochemistry and Molecular Genetics at Northwestern Medicine. He's a urologic surgeon with expertise in the diagnosis, treatment and management of bladder cancer.
Dr. Meeks, it's a pleasure to have you join us today. I'd like you to start by telling us why has checkpoint immunotherapy historically been more difficult to use to treat bladder cancer? What is checkpoint immunotherapy and why are biomarkers of response to immunotherapy needed?
Joshua J. Meeks, MD: Hi. Great to talk, Melanie. Thanks for having me on. This question really kind of comes from a real sticking point with how we take care of our patients at Northwestern and across the world really. This bladder cancer is a very aggressive cancer and, in general, around 17,000 to 18,000 patients in the US are going to die from bladder cancer. We tend to think that, while surgery has one part, trying to care for patients with cancer that leaves their bladder and spreads to the rest of their body is really where the fight's going to be won or lost. And up until the early 2000s, the Nobel Prize for the immunotherapy was awarded in 2018. So, that gives you a sense that really this is a new revolution of therapies. And the whole premise of this is that as these cancers develop, they're sort of waging a war with your immune system, and they're smart enough where they're able to turn off the features of the immune system so that the immune system kind of goes to sleep and doesn't recognize a cancer as being foreign. It thinks it's part of the host of the body. The drugs work by turning off these off signals. So, it's a double negative. It actually turns on the immune system to recognize the cancer and come after it. And so, these therapies, you know, again, I've got loads of patients who are alive who have prolonged survival just because they happen to be alive when these therapies come around. The problem though is that most responses are not durable and, long term, the response rate is around 20-30%. You get an initial stabilization. But realistically, only one in three patients will have a long response to immunotherapy. And the challenge is, number one, trying to identify that third. And the other part is, are there better therapies we should be using to add to immunotherapy to let them work better?
Melanie Cole, MS (Host): Thank you so much, Dr. Meeks. Do any biomarkers exist as of now that can help guide treatment decisions about immunotherapy? Tell us about your published research in Nature Communications that describes this biomarker signature test to predict which tumors will respond to immunotherapy. Tell us about the study and how your team identified this biomarker.
Joshua J. Meeks, MD: So, that's kind of what we ask with study. So, all of this work really was a multi-institutional and a multinational collaboration. So, we started working with a group out of Milan, Italy. The investigator's name was Andrea Necchi. He had the first real trial in bladder cancer where a patient comes in with a tumor, and then you give the patient a therapy called pembrolizumab, which is a form of immunotherapy. And then, the patient has surgery to have their bladder removed. And so, that lets you look at the tumor before treatment so you can get a bunch of analysis of that tumor, and then the patient gets treated. And then, you see did it work or not. And the key point is you can see when it didn't work, what were the resistance factors that were present. So, we started collaborating with him around 2018 or '19. They sent all the tumors from Italy to Northwestern. We did a full gene expression analysis on over a hundred patients and working with another scientist, his name is Gordon Robertson, who's in Vancouver. We sort of did a bioinformatic analysis to figure out could we identify not just who responded and who didn't, but mechanisms by which patients could or could not respond. And that really helped inform us to figure out, well, there's probably at least two ways that cancers are resistant and maybe three ways in which they respond and they're very different. And from that, we can start to figure out, again, next sets of therapies and really trying to piece this whole story together.
So again, we, were able to look at the tumors themselves. You know, we did little biopsies, extracted all the RNA. And then again, a lot of it is a lot of long kind of computational lifting to group the tumors together to sort of understand if you look at all the tumors that respond, did they look the same and no, they didn't. There's a couple different sets of pathways that show up. And I think what we can do with that and what we did was actually collaborate with another scientist, Clair Groeneveld, who is in Paris, to figure out could we set up a biomarker that we could look prospectively at tumors and say, if a patient shows up today, can we look at their tumor and say, "What are their chances of responding?" And that's really where we'd hoped this would go. We have patients every day making decisions about should they take immunotherapy or not. And honestly, it's a question of risk-benefit. Is the toxicity of the therapy going to be worth the potential benefit? And if you could tell someone, "I think you have a good chance of responding," then that risk is worth taking. Right now, it's a little bit of a blinded walk. And again, only 30% have a response and, otherwise, they're all just sort of risking toxicity. So, that's really where we're hoping to go with this.
Melanie Cole, MS (Host): Well then, other than optimizing treatment selection, Dr. Meeks, are there other potential benefits and/or downsides for bladder cancer patients that you work with them in that shared decision-making decision?
Joshua J. Meeks, MD: One of the more discovery parts of our study was that we could take some of those non-responding cancers. We were able to sort of identify a few pathways that were sort of aberrant. For example, one of them was a gene called FGF receptor 3. And there's drugs that target that. We don't have to think about just giving immunotherapy. You could say, "Well, we can combine therapies that target those vulnerabilities with immunotherapy." And there are trials out there that are going to start doing that. So, our hope would be to say, "Well, this therapy may not work completely, but what if we put a couple of these together to try to increase the robustness of the response?"
Melanie Cole, MS (Host): Well then, take us from bench to bedside, Dr. Meeks. How will your findings aid other physicians to determine which patients are likely to respond to immunotherapy? I'd like you to speak about how this will impact not only patient care and their journey down the line, but research down the line because it's absolutely fascinating.
Joshua J. Meeks, MD: Yeah. And I'd say where we're at with immunotherapy and bladder cancer is that there was a huge boon and a lot of these drugs received accelerated approvals. And then, gradually, a lot of that has receded away because we found that long-term the responses for many patients are just not durable. So, where we see this fitting in is that we think that if you take a hundred patients and only 30% respond, it's hard for those other 70 people that don't respond. But if you could identify those people ahead of time and say, "We have good precision to predict who will respond," then that really makes it a really viable option for them. So, what we're thinking is that where there is a possibility for immunotherapy, we could potentially use this test to potentially increase the response for patients.
Melanie Cole, MS (Host): I'd like you to wrap up for us by describing any clinical trials that will be starting at Northwestern Medicine within the next year, and your hopes for the future to develop novel therapies to improve survival of patients with bladder cancer. These are such exciting results and you're doing such amazing work. I'd like you to speak to other providers, Dr. Meeks, and tell them what you would like the key messages from this episode to be.
Joshua J. Meeks, MD: Yeah, I think the steps going forward is that we have a real luxury to have another form of therapy. The second wave of treatments for bladder cancer really involve these immunotherapies. But I think what we're finding is they're not a shotgun where we can apply them to everyone. They're going to be much more like a sharp shooting rifle where we have to know which patients will have the best response. And so, our hope is that we'll continue to be able to use these therapies, but provide them in the right manner. And hopefully, this work from our biomarker investigation can really try to identify those patients.
Melanie Cole, MS (Host): Thank you so much, Dr. Meeks. As always, you are such an excellent guest and so informative. Please join us again and give us updates as these and other clinical trials continue to proceed. So, thank you again. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/urology to get connected with one of our providers.
That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.