Outcomes Rocket Podcast_Natera Series_Angel Rodriguez: this mp3 audio file was automatically transcribed by Sonix with the best speech-to-text algorithms. This transcript may contain errors.
Saul Marquez:
Hey everybody, Saul Marquez, and welcome back to the Outcomes Rocket! I’m so excited to continue this amazing series that we’re doing with Natera on Cell-Free DNA Diagnostics. Today we are going to be covering immunotherapy response monitoring with circulating tumor DNA testing. What’s the response? How does it happen? What works? What doesn’t? Today, I have the privilege of having Dr. Angel Rodriguez join us. He’s an oncology medical director at Natera, he’s a board-certified medical oncologist, and attended Baylor College of Medicine in Houston, Texas, where he completed his residency in Internal Medicine and fellowship in hematology and medical oncology. Dr. Rodriguez was the recipient of the Komen for the Cure Multidisciplinary Breast Cancer Grant and specialized in breast oncology at Baylor College of Medicine, where he conducted research in breast cancer stem cells, xenograft models, and gene expression profiling. Before joining Natera, Dr. Rodriguez practiced in Houston Methodist Cancer Center, where he was director of the Clinical Trials Office and also led the triple negative breast cancer clinic, so we have an expert with us here. With that, I want to welcome you to the podcast, Doctor Rodriguez.
Angel Rodriguez:
Thank you, Saul. It’s a pleasure to be here.
Saul Marquez:
Absolutely. So, you know, there’s, there’s certainly a lot of, a lot of questions in the field of, of oncology around response. How am I going to do, how are my patients going to do? And, and with that also comes a lot of waste with, with testing and waste with treatments that maybe aren’t the right treatments for the right people. So I know this, this topic is, is going to be of interest to a lot of folks listening. But let’s start with the basics, what exactly is immunotherapy and how does it work?
Angel Rodriguez:
All right, great, yeah, great questions and definitely a big clinical challenge, right? The two of the most important questions that we ask ourselves in the clinic, both with the patient then, and then from our perspective, is, can we try this immunotherapy, and is it working, right? So, so first we have to understand what exactly is immunotherapy and how does it work? So immunotherapy is a type of cancer treatment that boosts one’s own body natural immunity to fight the cancer. And first, I’ll describe a little bit about what is physiological, what is normal, to understand it better. Now, although we can live a healthy lifestyle and reduce our chances of developing cancer, the truth is that cancer can happen to anybody, even the healthiest of people. And when cancer develops in our body, cancer cells, well, they have strengths and weaknesses that allow it to survive, to grow, and well to create problems in the human body. Now, relevant to our discussion today is the fact that cancer cells form from existing normal, healthy cells in our body, and it can be from any cell, from any organ of the body. What is the role of our immune system? Well, amongst many things, it fights infections, and it does so by recognizing other cells as foreign, as bad, as cells that need to be attacked. How does our immune system recognize our normal, healthy cells and avoid attacking it? Well, because our cells have special proteins, we classify them as immune checkpoint proteins. And it’s kind of like an ID card that the cells show the white blood cells to prevent them from being attacked. And guess what? When cancer cells form, they too can adopt these membrane proteins that allow them to evade the immune system by showing them this ID card. And so the most well-known immune therapy drugs are what we call immune checkpoint inhibitors, basically drugs that take away the ID card from the cancer cell so that the white blood cells can attack the cancer cells.
Saul Marquez:
That’s fascinating. And I love the, the analogy of the, of the ID card. So these immunotherapy drugs strip away that, that false ID card and don’t let them.
Angel Rodriguez:
Right. That’s exactly right. And now, once the immune system finds these cancer cells, the cancer cells don’t have that ID card to show, hey, I’m a good guy, don’t attack me. If you take that away with these immune checkpoint inhibitors now, the white blood cells are free to attack them.
Saul Marquez:
Makes a lot of sense, makes a lot of sense. Thank you for that. How, how has immunotherapy changed the landscape of how we treat patients?
Angel Rodriguez:
Sure. So it’s been a remarkable feat, just a tremendous discovery, you know, from, from the bench to the bedside. So what, and for example, what used to be very difficult than aggressive cancers such as melanoma, lung cancers, kidney cancers, cancers that despite our best efforts with our traditional treatments like chemotherapy, which is sort of more of a shotgun approach, trying to attack cells that grow and with no specific mechanism, we now, these cancers can be highly treatable, they can be cured with immunotherapy, and clearly, we’ve improved the quality of life of many of our patients, we’ve extended the life of our many patients, and we have cured many patients because of immunotherapy. And then the discovery of immunotherapy has been so revolutionary that in, well, 2018, the Nobel Prize for Medicine was awarded jointly to two researchers, American Jim Allison and Dr. Tazuko Honjo from Japan.
Saul Marquez:
You know what? It really has sort of, it’s like specificity of the attack and versus the shotgun approach has really helped a lot of people. And so there’s challenges, too, right, so, so let’s talk about those. What challenges do doctors and patients face when being treated with immune checkpoint inhibitors?
Angel Rodriguez:
Yeah, at first, you know, you make a really good point, right? When it comes to the difference between a, a specific immune system sort of working versus a shotgun approach. So now I’ll shift gears and kind of talk a little bit about what are the challenges. As I mentioned, these have been, I mentioned the good things, right, the good things about immunotherapy, that, that it can work, that it can shrink cancers, it can eradicate cancer. But with the sad reality, going back to our original questions is one, should I try immunotherapy in my patient? And then once I’ve decided and chosen, yes, I’m going to try it, is it working? Because sadly, the big challenge is that immunotherapy does not work in all cancers, and immunotherapy, the effect doesn’t last forever on all cancers. So now we have to, now that we’ve identified, so there’s, there’s challenges in what we call biomarkers, which is that test that we do on the tumor tissue to try and figure out will this patient benefit from immunotherapy? And even then the best biomarkers that exist today, you know, it may be that only 30% will benefit or only 40% will benefit. So, so again, what we know going into immunotherapy that it may not work in about 60%. So then how do we tell where is it working, where it isn’t, where should we continued, because if we, if we pick wrong, if we choose wrong and we continue treatment that is not working, then all we’re doing is exposing the patient to increased side effects, which is, of course, the other challenge. If, if immunotherapy would not have any side effects whatsoever, well, then, great, let’s just try it on everybody and see what happens.
Saul Marquez:
Yeah.
Angel Rodriguez:
But it’s not, it causes side effects. You know, any, anything that is sort of autoimmune in nature, for example, can happen, it can attack your lungs, it can attack your liver, it can attack your joints, it can attack your thyroid. And so whenever we can avoid that from happening to our patients, it would be a win. If we can avoid that in patients who, the immunotherapy is not working, and we can try something different.
Saul Marquez:
Yeah. And so, you know, in the in, in this series with Natera, we’ve sort of been, been covering a lot of opportunities to, to fine-tune these therapies so that they actually benefit people. As far as Natera goes, is there a test that you guys offer to identify if it’s going to be effective? Can you tell us about the probability of effectiveness? It would be interesting to hear that.
Angel Rodriguez:
Yeah. So this is not where our two worlds collide. Why is it that Natera is so involved with, with, in oncology and specifically in, in cancers that are treated with immunotherapy? Right, so we’ve talked about the challenges that exist today in the clinic with immunotherapy. And so now here comes this very powerful blood test that is called Signatera, it is a test that is purposefully built to detect molecular residual disease or to detect the tumor burden at a molecular level and can be tracked over time. And so what’s unique about the test is that it is personalized and it’s also what we call tumor informed. So it’s a blood test that is unique to each patient, no two patients have the exact same blood test. And so right, when we talk about all the different discoveries in cancer, it’s about us exploiting the weaknesses of cancer, right? So we talked about immunotherapy, the fact that cancer cells can be attacked by the immune system, we exploit that weakness and discover immunotherapy. So what also happens with cancer is that it kind of gives itself away by shedding some of the fragments of its DNA to kind of dump some of the, its junk into the blood, as little pieces of DNA fragments that we can take advantage, we can extract it, find it, quantify it, and then ultimately, tell a patient, a doctor, hey, there’s still cancer left behind and we’ve measured it and this is how much is there. And so that’s what we’ve sort of taken advantage of and developed this test that quantifies the circulating tumor DNA fragments within a patient that is unique to that patient’s cancer. So now that we can quantify it and when we give treatment, then we can assess whether the levels are going up or whether the levels are going down. And, of course, it doesn’t take a genius to know that when it’s going up, it’s bad, when it’s going down, it’s good.
Saul Marquez:
Yeah.
Angel Rodriguez:
And we have been very fortunate to have collaborated with many different institutions around the world. And in particular, one of our big collaborations was with Princess Margaret Cancer Center in Toronto. And so a publication that was, that was in Nature Cancer in 2020 was a collaboration between Princess Margaret Cancer Center and Natera. And what we did there was evaluate the performance of Signatera in, as far as predicting treatment response in a group of patients who were treated with immunotherapy.
Saul Marquez:
Got it. So then, there’s, am I hearing two things then? On the one hand, it’s effectiveness by understanding the count in the test, and then the other piece is, is predictive in nature? Are you going to do well with this?
Angel Rodriguez:
Yeah. So okay, so that’s a very good question, and so as a clinician, as a patient, when we’re making the decision to start treatment, we have to have these information prior to starting treatment. And so blood or tumor tests like immunohistochemistry, you know, PDL1s, sort of these protein tests that we can analyze on the tissue allows us to ask the question or answer the question, should we even try immunotherapy, right? And roughly, if a test tells us that we have a 0% chance it’s going to work or less than five, less than 10% chance it’s going to work, we typically say we’re not even going to try it, okay? Now, Signatera comes in once you’ve made the decision to, okay, we’re going to start immunotherapy. Well, now we have this dynamic tumor marker that after a dose or two, you can look at the levels, see if they’re going down, see if they’re going up, and if, because of the mechanism of immunotherapy you’re seeing the levels go down, chances are that that patient is benefiting and is doing well. So in that collaboration, that study that I, that I, that we talked about, it was a study called the Inspire Trial. And patients received the immunotherapy every three weeks, and in this case, it was pembrolizumab. What we were able to demonstrate was that looking at the ctDNA levels, comparing them baseline to week six, which is after just two doses of immunotherapy, if patients had an increase in ctDNA, then only 2% of those patients eventually had a response to treatment, only 2% eventually had response to treatment. So 98% of patients did not have any benefit to that treatment. And, but also more importantly was that there were roughly 12% of patients who completely cleared their ctDNA, right, at the molecular level after they started immunotherapy, you checked again and you couldn’t, you couldn’t find any molecular evidence of immunotherapy, and so for that cohort of patients, those patients had a 100% overall survival at roughly two years. So again, if you clear your ctDNA, once you start immunotherapy, your outcome is going to be phenomenal.
Saul Marquez:
That’s great. Thank you for explaining that. Those two areas, one, understanding if you’re going to do it and then Signatera steps in and can tell you, is this working, is it not?
Angel Rodriguez:
Exactly, exactly.
Saul Marquez:
And is going to be effective?
Angel Rodriguez:
Exactly. And I also want to clarify that it’s not meant to be used on its own, right? It’s meant to complement what we already do in the clinic today.
Saul Marquez:
Yes.
Angel Rodriguez:
So how do we assess, and actually, it’s kind of rudimentary, well, how do we know if a patient’s benefiting from treatment or not or whether I should continue? Well, we do CAT scans, you know, and what we are uncovering now with the biology in terms of what this tests, the biology that this test is uncovering, right, by looking at levels go up or down is that, is that scans are not perfect, imaging scans are not perfect, we’ve actually, actually known for some time that immunotherapy, in many cases, when it works, it looks like the mass is growing on a scan and it looks like it’s growing, and one may think that it’s because the cancer is growing, but in reality, the mass is growing because it’s being infiltrated by white blood cells, and therefore the immune system is actually working. It looks like it’s growing, but it’s growing because of good white blood cells attacking the cancer. And so in the past, it was challenges, you know, who’s, who should I continue? Who should I stop and switch, right? The worst thing you can do is it’s working beautifully and then you stop treatment because you think it’s the cancer is growing. But then this test, when you do it in conjunction with, with the scans, is when it can be very powerful. So another highlight sort of result that, that, that came out of that publication, that that collaboration was that patients who had an increase in the size of the mass by a scan as well as a rise in the ctDNA levels, zero patients, none of the patients eventually had a response to treatment. So thus we were actually able to distinguish with what we call true progression of the cancer versus what we call pseudo progression, false progression.
Saul Marquez:
Yeah. And that exactly what was going through my mind was it’s a false positive, right? When you when you have a CT that shows an enlarged tumor, it’s a false positive, potentially, right? If there’s, if decreased counts with the test, right? Yeah. Oh, my God.
Angel Rodriguez:
That’s exactly right, that’s exactly right.
Saul Marquez:
I mean, and and as a clinician, how great to have a tool like this to be able to deliver therapies confidently or to stop them if we know that they’re not working.
Angel Rodriguez:
So that’s exactly right. And I think so today, this is a test that, as I mentioned, can complement what we already do with the patient. And I think, right, it’s not just about what the levels are doing, what this guide is looking like, you also want to see the patient as a whole, of course, how is the patient feeling or are they having any symptoms? Do we have any room at all to potentially allow for progression of the cancer, right? If you’re talking about a one and a half centimeter cancer, that there’s no urgency to switch treatment, right, and that one, you could potentially ignore the fact that maybe it’s growing a little and the levels are going up. But if you have a patient where the liver is riddled with cancer and you really need to know for that patient if the treatment’s working, because you know that if the cancer is growing, you’re going to miss the opportunity to try that second, second therapy after immunotherapy, try another option, and that’s the other key, right? We need to have also good, effective treatment options that can replace the immunotherapy that’s not working. So you put all of that into context, it gives you a better sense, a better discussion with the patient, better informed consent to decide, am I going to continue or am I going to stop? And also, you know, what’s exciting is what, you know, what the future of clinical trial designs are looking like with, where they are putting more emphasis on ctDNA changes and they are in the CAT scans.
Saul Marquez:
Well, this is fantastic. Dr. Rodriguez, I really appreciate your your insights here and walking us through how immunotherapy works and things that, that clinicians and patients alike could, could benefit from. What, what closing thoughts would you leave us with? This has been this has been a great, great interview.
Angel Rodriguez:
Yeah. I mean, I think the future is bright with how we are continuing to improve the lives of our patients with cancer, whether it be improving quality of life or whether it be further increasing the chances of, of a cure. And one thing that we didn’t highlight in this particular podcast, maybe we could save it for another one, is the fact that after a patient, right, mostly we’ve been talking about patients who have metastatic disease, where the immunotherapy treatment is palliative in nature. Well, the applications in the setting of somebody who has received curative intent, let’s say surgery, to answer the question, did that patient, does that patient still have disease at the molecular level that cannot be seen in scans? And will that patient benefit from additional therapy, such as immunotherapy? Or patients that today are being treated with chemotherapy after their surgery, but in reality, they don’t need it. They’ve been cured with surgery, and this test shows that there isn’t any evidence of molecular disease, you know, those studies are ongoing to be able to then ultimately prove sort of one of the questions you ask is that it’s also predictive. So only those patients who have residual, just, just a positive test after surgery are the ones that will benefit from immunotherapy or benefit from chemotherapy. And so we’re really excited that over the next coming years, data from, from landmark studies will, will we’ll be reporting out.
Saul Marquez:
Well, that that is fantastic. And Angel, maybe we do a part two of this because that in itself would be a fascinating discussion. And folks, don’t worry, there’s, there’s so much that Natera does, and Dr. Rodriguez and his team do to, to inform and educate, just go to Natera, their website, there’s a link in the show notes. Learn more there, don’t let this be the end of your learning. Dr. Rodriguez, just want to say thank you so much and really appreciate what you do!
Angel Rodriguez:
All right. Thank you so much, Saul, it’s a pleasure to be here, thank you.
Sonix has many features that you’d love including share transcripts, automated transcription, automated subtitles, secure transcription and file storage, and easily transcribe your Zoom meetings. Try Sonix for free today.
