How Can a Treatment Become a Vaccine??? Dr. Peter DeMuth, Chief Scientific Officer at Elicio Therapeutics
There are few things more anxiety producing than having to go in and get a scan to see if your cancer may have returned. And thankfully, scans do pick up tiny tumors. But what if we could see characteristics of that cancer much earlier while they were simply individual cancer cells? And what if that ability might lead directly to a treatment or even a vaccine, recognizing and eliminating those cells should they appear in the future? Today, we learn how Elicio Therapeutics is working to do just that.
Dr. Moira Gunn:Doctor Peter DeMuth is its chief scientific officer. Doctor Demuth, welcome to the program.
Dr. Peter DeMuth:Thank you. It's great to be here, Moira.
Dr. Moira Gunn:Now I've been thinking about a place to start and I'm hoping this is the right place. You know, we we've all heard about DNA, but you use the term ctDNA. What is ctDNA?
Dr. Peter DeMuth:Yeah. That's a great place to start. So ctDNA stands for circulating tumor DNA, and this is DNA that is released by tumor cells that might be present in the body. And some of this DNA, when it's released, is able to make its way into the blood. And then it can be detected with a specialized test that analyzes a patient's blood.
Dr. Peter DeMuth:And these tests are really interesting because they're based upon a DNA signature that's found in the tumor. It's specific for the tumor almost like a fingerprint. So these tests are designed to work by detecting that DNA signature of the tumor in the blood so that if we see this fingerprint in the blood test, it tells us that a tumor is present somewhere in the body.
Dr. Moira Gunn:Now is this new technology? Have we been using it for some time? Where are we with this?
Dr. Peter DeMuth:It's it's relatively new. We're definitely seeing progress, and these types are types of tests are being designed and perfected over time. So we're looking to improve the way that we can detect cancer using these ctDNA tests, and the other really interesting opportunity is to use them to, inform the treatments that we design for patients. So taking a big step back right now, most of the time, cancer patients are diagnosed using medical imaging techniques. And this can give us important information about a tumor, can show it us where it is or how advanced it is, and it can even be used once patients are on treatment so that we can monitor the tumor, and it can tell us whether the cancer is responding to a particular therapy.
Dr. Peter DeMuth:Is it getting bigger? Is it getting smaller? Is it completely gone? So imaging is really useful, but these ctDNA tests could be used in many of the same ways to detect a tumor, to learn something about the tumor, to understand if a treatment is working, but the ctDNA tests have some really important advantages. So this might help us to treat cancer more effectively.
Dr. Peter DeMuth:One of the big advantages is that because ctDNA tests use blood, they can be more convenient than going for repeated medical imaging. But also, and this is the big one, ctDNA tests can be extremely sensitive. So for example, medical imaging might only be able to detect a tumor that is about a centimeter in size, but since ctDNA tests are based on DNA, they might be able to detect the presence of a much smaller tumor that would not ordinarily show up on a medical scan. And the reason this is important is because with cancer, treating early when a tumor is small and more manageable gives us the best chance to be successful. So, overall, it's really exciting to see these tests being used more often and in different ways, and I think that could really help improve patient care.
Dr. Moira Gunn:Now do we have to know the tumor profile, the tumor DNA for a particular person to compare it to see it in the blood?
Dr. Peter DeMuth:Yeah. Many of these, tests are built upon, an analysis of a tumor that's done early on when a patient is first diagnosed, and then that information is used to develop the fingerprint that I mentioned, the signature of the tumor, and that signature is what is analyzed in the blood. So some of those tests are built on that concept, but others use more basic information that is shared and common across many different tumors in many different patients.
Dr. Moira Gunn:So let's say I have cancer surgery. If all the cancer is removed, then we should not see any ctDNA in my blood. Right?
Dr. Peter DeMuth:That's exactly right. So if a tumor is truly completely removed by surgery or it's destroyed by a therapy that's effective, there would be no tumor cells left in the body to produce that ctDNA. And in that case, the ctDNA test would be negative. It would show no detectable levels of ctDNA or presence of that tumor signature in the blood.
Dr. Moira Gunn:And going on from here, if there are cells that are remaining, will they continue to grow and we eventually see their ctDNA?
Dr. Peter DeMuth:Absolutely. And I can give you a really good example of this. So one area where ctDNA tests are being used is to evaluate patients after surgery. So, of course, the goal of surgery is to completely remove the cancer, but, realistically, that can be very difficult to do. So ctDNA can give us a very sensitive tool to determine whether there's tumor remaining after surgery.
Dr. Peter DeMuth:So if ctDNA is present, we refer to that as molecular relapse. So this is because we can see the signature of the tumor on a molecular level, And this is often at a point where standard medical imaging may not be able to detect that tumor at all. So by using this approach, we've seen that patients with molecular relapse after surgery, they're more likely to develop that visible tumor on their scans, and this happens much more quickly compared to patients that don't have detectable ctDNA after surgery. So having this information gives us a really good opportunity to treat these patients earlier when the overall amount of tumor is small and the goal, is to see that ctDNA level decrease or, best case scenario, go away completely. And if we're able to achieve that, the expectation is that we could prevent recurrence of the tumor and patients might have longer and healthier lives.
Dr. Moira Gunn:Now let's get to what Eliseo is doing. What are you doing?
Dr. Peter DeMuth:Yeah. So till now we've talked about how we can determine the DNA signature of a tumor as part of that ctDNA test. But the tumor signature is important in other ways. For example, it could give us clues about what parts of the tumor we can target with treatment. For example, what parts of the tumor differentiate it from normal healthy cells, and these differences could be really good targets for a potential treatment.
Dr. Peter DeMuth:So our goal at Alesio is to use that information, that signature of the tumor, to train the immune cells of the body. Essentially, we want the body's own immune cells to use that tumor signature to identify cancer cells specifically and then to destroy them. And it's probably helpful to pause here and say something quickly about the immune system. When we talk about the immune system, what we really mean is the millions of immune cells that are present in our bodies, and there are different types of immune cells. Each cell type has a function and a job, and overall, these cells work together to protect us from infectious disease, bacteria, from viruses, but they can also protect us from our own cells if they become mutated and have the potential to become cancer.
Dr. Peter DeMuth:So one of the jobs of the immune response is to detect these mutated cells and, ideally, to kill them before they're able to become cancer. And one particular type of immune cell I wanna mention is important for this. Some people may know these as t cells. But if not, what you need to know about these cells is that they patrol throughout the body. Part of their job is to recognize the mutations that develop in cancerous cells.
Dr. Peter DeMuth:In other words, they could detect if a cell has that signature or that fingerprint that's associated with cancer. And with the right training, they can search out and destroy those cells. So to bring it all back, the idea at Alysio is to design treatments that can train these immune cells so they can first recognize that cancer signature and have the ability to kill those cancer cells wherever they find them in the body.
Dr. Moira Gunn:So you're smartening up these t cells, these immune cells, and they're trans they're all over your body looking. Looking looking looking looking.
Dr. Peter DeMuth:That's exactly right.
Dr. Moira Gunn:I feel like my body is so smart. Make your body smarter. It could be your model. It could be your model.
Dr. Peter DeMuth:We often call the lymph nodes the schoolhouse of the immune system for that exact reason. We're taking these immune cells to school.
Dr. Moira Gunn:Now you just mentioned your lymph nodes. What do what do they have to do with with these these immune cells, these t cells you're smartening
Dr. Peter DeMuth:up? That's a great point, Moira, and and I'll get to that. Let me first start by talking to you about these signatures a little bit more. One of the main signatures that we're looking for in the cancers that we're trying to treat is called KRAS. KRAS is a mutation present in many different tumors.
Dr. Peter DeMuth:It's part of that tumor signature. In fact, it's present in about 20 5% of all human solid cancers, including pancreatic and colorectal and lung cancers. And in total, these mutations affect cancers that are present in 100 of thousands of patients in the US every year. So if we could design a treatment that would take those immune cells to school, train them up so that they recognize that mutant form of KRAS, these cells would then be able to go out and destroy those cancer cells throughout the body. For for example, they could be useful to to eradicate cancer cells that could be left over after surgery and prevent those cells from growing and causing recurrence of the tumor.
Dr. Peter DeMuth:So let's get to the lymph nodes, as you mentioned. So training these immune cells is a big challenge, and the lymph nodes, we believe, are the solution to that challenge. So the average person might not think about lymph nodes very much, but they're very important for the immune response. These are the primary sites in our body, where the immune cells come together, where they exchange information with with each other. They serve as training centers for the immune response.
Dr. Peter DeMuth:So in essence, where the immune cells coordinate all the activities that they need to perform to defend the body. So the strategy at Alysio is to get these types of treatments to the lymph nodes, and that has been a big challenge. Typically, these types of treatments, after they're dosed, they're diverted away from the lymph nodes, and so they might miss their chance to train those immune cells. But what we're doing at Alysio is developing a new class, a new type of treatment that are targeted directly to the lymph nodes where we can train those immune cells more effectively. And this is something that has taken a lot of work.
Dr. Peter DeMuth:And the strategy that we've developed is based on albumin, this very common protein in the body, which has a very useful property in that it travels very specifically precisely into the lymph nodes. So we're looking with our approach to take advantage of this, and we can do that by engineering our treatments to attach to albumin after they're injected, and this allows us to directly target those treatments to immune cells in the lymph nodes. So the idea here is that once in the lymph nodes, those treatments can educate immune cells so they recognize the tumor, and those cells are able to patrol throughout the body, search wherever they find cancer cells, they're programmed to kill them, and do that specifically while leaving normal healthy cells untouched. And if we're able to do that, we've got a really good shot at at treating cancer effectively.
Dr. Moira Gunn:So you're taking albumin, which we've all heard of, you know, is very common in the body, and you're engineering that signature onto the albumin, then the albumin goes into the lymph node and says, hey, this is what you gotta The back end says, this is what you gotta look for. That's what's making the t cell smart?
Dr. Peter DeMuth:Yeah. That's exactly right. This is this is all about delivery. We have information that we wanna get to the immune cells, and albumin is able to get that information directly into the place where the immune cells are are where they are and where they can use that information to develop the right responses to treat cancer.
Dr. Moira Gunn:So you're also making smart albumin?
Dr. Peter DeMuth:Well, albumin is already smart. You're just taking advantage of the things it knows how to do really well.
Dr. Moira Gunn:Alright. Alright. We're there. Now, I know you're in phase 2 for pancreatic cancer. Every phase 2 started with a phase 1.
Dr. Moira Gunn:Let's take us back there so we know what you did in phase 1. Who you looked at, the humans you looked at, what you tested, and what you learned.
Dr. Peter DeMuth:Yeah. So I'd love to do that. The phase one trial was looking at 25 patients with pancreatic and colorectal cancer, a group that is in significant need of new therapies. These patients had already been through the standard treatments. So in this case, that's chemotherapy and surgery to remove their tumor.
Dr. Peter DeMuth:And after that, they're evaluated using medical imaging to understand the state of their cancer. We're essentially looking to see if we can find any tumor remaining. And for patients coming on to the trial, the answer there was no. The scans didn't show anything. We can't see a tumor, but, this is a big but, when we look with that more sensitive ctDNA blood test, we see the tumor.
Dr. Peter DeMuth:We're able to see that those tumor cells are still present, and, unfortunately, this means that the cancer is likely to return and at that point to progress really quickly. So with this information, what we asked was, can we treat those patients to eliminate the remaining tumor cells that we detected with the ctDNA test? And by doing that, could we potentially prevent the cancer from returning? So that's exactly what we tried to do, and we saw some really interesting things. So the the first thing we saw was the immune response.
Dr. Peter DeMuth:We, in this case, wanted to count, essentially, to count the number of tumor killing immune cells that were present in these patients before and after the treatment. And what we saw was that after treatment, the number of immune cells was increased in the vast majority of the patients on that trial. So, obviously, this suggests that the treatment is doing a good job of training up those immune cells. After that, we wanted to see whether patients had reductions in the level of their ctDNA, and we saw that that was the case in many patients. In fact, almost a quarter of the patients completely cleared their CT DNA, which means it went to 0 undetectable.
Dr. Peter DeMuth:And so that is suggestive that the residual tumor cells that were present after surgery were being killed. And what's really exciting, the last thing we wanted to do was see whether the strength of the immune response, the number of immune cells, was in any way connected to how well patients did overall. And so what we did is we looked at the time that patients would take to relapse or to pass away from their disease and measured that against the strength of the t cell, the immune cell response. And what we saw was that there was an 86% decrease in the risk of recurrence of death or relapse in patients that developed the strongest, the best immune cells to our treatment. So this is obviously really exciting, and it shows that the treatment is both generating those immune cells, training them up, and that if patients get those types of responses in their immune system, they may be able to delay or prevent the return of their cancer.
Dr. Peter DeMuth:So, obviously, now our job is to confirm that in the phase 2 study.
Dr. Moira Gunn:And as happens in phase 2, you look at what happened in phase 1, and you don't just continue it. You say, okay. Maybe we'll target this or maybe we'll change this. And so while you will, at some point, work on colorectal, you decided in phase 2 just to focus on the pancreatic cancer. Now tell us what that is and how that's different.
Dr. Peter DeMuth:Yeah. That that's exactly right. So the phase one look at both. We have to make a choice in phase 2, and we chose to look at pancreatic cancer. And there's some good reasons for that.
Dr. Peter DeMuth:We know that pancreatic cancers are often mutated with this KRAS mutation, so they have the exact signature that the treatment was designed to address. So many patients with this type of cancer could benefit. We also know that pancreatic cancer is one of the deadliest cancers. It has a 5 year survival of less than 20%, so patients are in in very great need of new therapies. So in this trial, the phase 2, we're again looking at pancreatic cancer patients, again looking at patients that have completed their standard, treatments, either chemotherapy or surgery, both most likely.
Dr. Peter DeMuth:And, again, the standard approach here is observation. So doctors are just waiting. They're monitoring. They're looking for that tumor to return, and they know that it will. So in the trial, instead of just waiting, instead of just watching, we're gonna look to see if this experimental treatment can delay or even completely prevent the return of the tumor.
Dr. Peter DeMuth:And, again, because this is a phase 2 study, we'll have the opportunity to compare the outcomes in those patients, the ones that get the treatment, to those who receive the standard observation. And this will allow us to measure how well the treatment works.
Dr. Moira Gunn:And how many people are in that study?
Dr. Peter DeMuth:Approximately a 135. So patients will be split to either get treatment or to get observation, and then we'll be able to follow them again to look for the amount of time that it takes for patients to have a recurrence of their tumor or to pass away, and that will give us a chance to observe the benefits that we could potentially see with this treatment.
Dr. Moira Gunn:And if they're not getting Eliseo's treatment, they're still getting all the other treatments that they were
Dr. Peter DeMuth:That's exactly right. Be.
Dr. Moira Gunn:Designed to be given. Yeah.
Dr. Peter DeMuth:Exactly.
Dr. Moira Gunn:So no one is without treatment in this?
Dr. Peter DeMuth:That's exactly right. Yes.
Dr. Moira Gunn:That's great. Now you keep saying if they got the treatment. Is this a onetime delivery?
Dr. Peter DeMuth:So the treatment is, multiple doses. So we give 4 doses in the 1st month and 2 additional doses in the 2nd month. And so this is the initiation, the first the first training session for the immune response, if you will. And then we give those immune cells a little bit of a break, and then we come back in and we train them again. We give them another 4 doses.
Dr. Peter DeMuth:So, essentially, another lesson, another, another session to learn the the lessons that we're trying to teach them.
Dr. Moira Gunn:So, you know, this really is science. We have to figure out how much is too much, how much is too little, how much is enough. There's there are questions here.
Dr. Peter DeMuth:Absolutely. Yes. There there are tons of things we're still learning. One of the really interesting questions here is how many immune cells we need to be effective? Also, what sort of qualities or functions those cells need to have in order to be effective killers and finders of tumor cells in the body.
Dr. Peter DeMuth:And I think the biggest thing that we're most interested to study, and that's the main goal of the phase 2, is, again, whether this type of treatment could prevent the cancer from turning from returning, and if so, how long that that protection might last.
Dr. Moira Gunn:So this starts out as a treatment because you're treating cancer that is present. And if it prevents it in the future, it becomes a vaccine.
Dr. Peter DeMuth:That's exactly right. So this can prevent the return of cancer in the future, but it certainly starts out in your body as a treatment. And this is one of the most amazing things about the immune system, essentially that it has a memory, that it can remember the past dangers that it's experienced before. And this is really important because it means that the immune cells that remember can react more quickly to protect you from threats that you might see again in the future. So, certainly, while this treatment is designed to address cancer that's present now, the immune system can form that long lasting memory, and it might be able to recognize future cancer cells and then prevent them from returning and causing the disease to progress.
Dr. Peter DeMuth:So it's certainly a really exciting opportunity to treat patients, but also to give them potentially really long lasting and durable freedom from disease.
Dr. Moira Gunn:So any future cancer with a KRAS mutation, hopefully, it would say you might be a completely different cancer, but we have you. But there are other mutations and other unique mutations.
Dr. Peter DeMuth:Yeah. Absolutely. There are many different mutations. Cancers are very diverse. So this is the type of therapy that could be used to target those other signatures of the tumor, and that's kind of the exciting part looking into the future.
Dr. Peter DeMuth:We're learning how to train these immune cells. We're teaching them how to see tumor cells behind them and destroy them. We've worked really hard, and we're we're still working hard to overcome this challenge of getting to lymph nodes. And if we do that, it looks like we can really help to train the immune cells and equip them to do the right things and find and kill cancer. So as we learn more, as we we understand more what makes a tumor tick essentially, we can develop these types of treatments specifically for different types of cancers and go beyond even the KRAS cancers that we're treating right now.
Dr. Moira Gunn:Well, doctor Demuth, this has been terrific. I hope you'll come back and keep us updated.
Dr. Peter DeMuth:I look forward to that, Moira. Happy to.
Dr. Moira Gunn:Doctor Peter Demuth is the chief scientific officer of Eliseo Therapeutics on the web@elicio.com. That's elicioelicio.com.
