Cancer-Fighting Bubbles with Eli Vlaisavljevich

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Travis

There are very few people who have not been touched in some way, shape or form by cancer.

So when I heard about Virginia Tech's Eli Vlaisavljevich's work to develop a focused ultrasound therapy to treat cancer by inflating and then collapsing bubbles under a person's skin, I had no shortage of questions. And thankfully Eli was kind enough to answer them all. Eli is an associate professor in the Department of Biomedical Engineering and Mechanics, and he also leads the Therapeutic Ultrasound and Noninvasive Therapies Laboratory.

The lab's overarching goal is to investigate the physical mechanisms related to ultrasounds and how they interact with tissues in order to develop non-invasive therapies for a whole wide range of clinical applications. He will help me understand how this form of focused ultrasound therapy called histotripsy actually works. He explained some of the prototypes he and his colleagues are developing to specifically treat liver cancer and some of the potential applications this work may have down the road for other forms of cancer in both humans and animals. And while the project itself innately has a lot of hope, Eli explained that it's also the collaborative and cross-disciplinary approach that he and his colleagues have successfully been able to take that really gives him hope for the future. So if potential life-changing medical treatments are something you're interested in, I think you will enjoy this episode. I'm Travis Williams, and this is Virginia Tech's Curious Conversations.

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Travis

So what is histotripsy? Let's just start there.

Eli

So histotripsy is a form of focus ultrasound therapy. So we in our lab develop, broadly speaking, focus ultrasound for wide range of applications, including, like you mentioned, the treatment of cancer. And histotripsy is really the highest pressure, the highest amplitude form of this therapy. So it uses sound waves to focus down to a single point in the body. And then we generate, unlike ultrasound imaging, which uses low pressure sound waves to image tissue in the body, we're using very high pressure sound waves that are focused to a single point. We generate these cavitation bubbles or this bubble cloud, and it non-thermally or mechanically basically destroys a tumor into a liquid or acellular debris. So it's basically liquefying a tumor non-invasively using imaging. But the word histotripsy actually comes from two root words. So histo, soft tissue, and tripsy is breakdown. So the breakdown of soft tissue and.

This was actually a technology that was invented at the University of Michigan where I did my grad school. So I worked in the first histotripsy lab there, and then we've really been growing it ever since I came to Virginia.

Travis

That's fascinating. you use this ultrasound technology to create bubbles into the skin. where, I guess, the sound wave creates the bubble. Is there air in my skin, in my body? Like where does that come from? How does it inflate the bubbles?

 

Eli

That's a great question. So it actually comes from the water inside your tissue. So all of our tissue is mostly water and inside of water we've calculated there's intrinsic nuclei as we call them. So these little tiny nanoscopic gas pockets that are just a property of water and we estimate they're about two to five nanometers in size. So it's the equivalent of when you boil water you increase the temperature until you get these bubbles that form. We're actually lowering the pressure such that we do that just with the sound waves, the pressure waves themselves. And if you get to a high enough peak negative pressure, we generate this explosive growth of these bubbles. So they go from these two to five nanometers, all within microseconds, they go to hundreds of microns in size, and then they collapse violently. And this is what causes that stress and strain that basically rips apart the cells in your tumor and kills them, mechanically.

Travis

Wow, and so where, you said it liquefies the tumor. Where does that go?

Eli

Yeah, that's another good question. basically what happens when we liquefy that volume, we've done a lot of studies that show like over time, it's just rapidly resorbed by the body. So you're basically just liquefying that volume. And if you look over the course of weeks and up to one to two months after that, that liquefied tissue just kind of resorbed by the body and it's just replaced by healthy tissues. So that's one thing that's pretty exciting. The other aspect is we're preserving critical structures, so vessels and bile ducts. So we're able to liquefy the tumor, get rid of that. And probably the most, I would say, surprising thing in my career, because I've always been excited about the potential of non-invasively destroying tumors, but we've actually seen as this liquefied volume is resorbed by the body, we see cases in a lot of our pre-clinical studies as well as clinically now that this has FDA approval for liver tumors, we actually see untreated tumors in some cases start to shrink because the body as it's coming in to clean up that liquid, it's actually activating a systemic anti-tumor immune response. So all of these systemic effects as a new therapy are still undergoing a lot of research for different tumor types, both clinically and pre-clinically. But a lot of excitement comes from the fact that we're just liquefying that volume. And because we're not thermally destroying the tissue, the body is able to come in and recognize kind of the components of that liquefied slurry.

So it has all this like broken down cells and proteins and fragments of the tissue and we're able to recognize that and understand how that affects the body system.

Travis

So let me make sure that I heard you correctly. You all break down this tumor and the body comes in and starts to clean up the mess that's made, but you realize that in the process the body's also like, so we want to get rid of these. And so it starts to take care of other tumors. Is that correct?

Eli

And it's something that doesn't happen every time and it's something we're exploring with different tumor types and how do we optimize the parameters of this. But yeah, really it opens up, it's like you're exposing tumor-associated antigens, other breakdown properties, so the immune system can then come and develop an attack on other tumors that we haven't treated yet. And so we're very hopeful that this can be combined with systemic therapies like chemotherapies or immunotherapy drugs as they're developed to advance from a non-invasive treatment for maybe one or multiple tumors in an organ to help address these kind of late stage cancers as well. So it's early, but a lot of exciting data on that that we're exploring to potentially take on really late stage patients where the tumor may have spread and you need something that can enhance the effectiveness of a systemic therapy in addition to a local destruction of these tumors that you can image and identify.

Travis

Yeah, that's amazing that the buddy's just like, okay, we're doing this now. We're getting rid of these now. That's awesome.

Eli

We work with a great team, many different collaborators. One of the main ones though is Dr. Coy Allen. He's an immunologist by training that's leading all of the immune work that we're doing here to really understand that process. He has multiple students in his lab working on different cancer types. Pancreatic cancer is one of the big ones we've been focused on collaborating with him. But trying to understand how can we harness these potential systemic effects in different tumor models and then our lab really brings how do we treat differently to maybe you know, elicit a bigger or smaller immune response for a specific tumor type. Is that correct? Yep. Yeah. Yeah. So we have a lot of collaborations with our veterinary hospital, both in, you his group is really focused on the preclinical side and then some of the work we're doing with veterinary clinical trials. So treating dogs with spontaneous cancers. So we have trials going for bone cancer, soft tissue tumors in dogs, brain cancer in dogs. And we're about to start our first equine. And he's in the vet school doing clinical trial for treating sarcoids and horses. So there's a lot of exciting applications for both humans as well as companion animals for us to develop this technique.

Travis

Yeah, that's great news all the way around. Well, you mentioned that this was invented at the University of Michigan, and that was where you were at when you found out about it. But it's my understanding that you've taken it and created the, I guess, the practical application or maybe created a prototype using this technology to treat liver cancer specifically. Is that correct?

Eli

Correct, yeah, so my PhD was focused in a couple areas when I was at Michigan. One was underlying the physics of this new technology, looking at how can we develop tissue selective therapy, so can we have blight tumors while preserving critical structures. And then the first big clinical application of my PhD was the treatment of liver cancer. And that started from the bench top setting all the way through doing small and large animal studies testing the safety and efficacy of this.

 

So when I finished my PhD in 2015, I actually spent two years working in industry for a company called Histasonics. And Histasonics was formed to spin out my advisor and others at the University of Michigan, these core inventors of hysterepsy, Dr. Jian Xu and others formed this company to spin out the technology. And when I basically defended my PhD, they decided, the company decided to focus all their efforts on liver cancer. So a shift from some of early work they were starting to pursue in prostate that showed good safety, but it wasn't a cancer indication. And so there was a lot of excitement about the data we had from my PhD to say, let's have a first application for liver cancer. So when I was at Histosonics, we basically developed the first early prototype device to go into humans. And then we did the TRISA study, which was actually named after my mom who died of liver cancer. That was the first human trial of histrepsy in the liver. That was done with our clinical teams that I still work very closely with in Barcelona where the trial was done, as well as University of Wisconsin and others who we partnered with on that trial. And so that showed good initial data in humans. Since that time, then I joined Virginia Tech, but since that time, Histosonics, and we still closely partner with them on this kind of more translational pipeline, they did what was called the HOPE for Liver clinical trial, which was a multi-center trial in the US and Europe. And that again showed success and led to FDA approval in October of last year. So it's been about one year. They've sold a bunch of devices. They're now treating people commercially. And so it's a very exciting time that we now have one approved clinical indication for histotripsy. There's a clinical trial going on for the treatment of kidney cancer right now. And hopefully within the next two months, we'll be enrolling and treating our first patients or histosonics will in their trial that we're partnering with them on for the treatment of pancreatic cancer. So that'll be the next after kidney.

Travis

Was there something special about the liver? I know you mentioned your personal connection to it, but is there something else special about it that made it a good, I guess, organ to target first with this technology?

Eli

Yeah, it's always a challenge when you, and this is why you see our lab is so big and we have so many indications. It's always hard when you have a potential platform technology that you think can work for so many indications. it's kind of a, that's probably the hardest part to decide where we're gonna put our efforts on. And that's why within cancer we have 10, 15 indications. Preclinically we're studying as well as treating blood clots, treating...So there's a lot of indications. starting at some times you have to, at some point you have to pick one and liver cancer has a lot of, a lot of reasons for choosing it that we're all involved. One, it's one of the fastest growing cancers globally. So there's a significant clinical need. There's a lot of technology that have been developed for the treatment of both primary and metastatic liver tumors. But, know, surgery is limited in most patients because these tumors are either at that too late of a stage, you have too many tumors the overall health of the patient isn't there or the tumor's located near critical structures like bile ducts, nerves, vessels. So it precludes surgery. There's thermal-based ablation that has shown some success in the liver, but again, it's limited not by those critical structures, because if you use heat to basically burn a tumor, it's gonna kill or damage vessels, ducts. So it limits the number of nodules you can treat as well as the size of the tumor. So there was really this big clinical need.

 

And then this, you know, the potential to advance beyond where the current therapies are to address that need with histotripsy. That's kind of why we started in the liver. But, you know, it's kidney cancer, pancreatic cancer, obviously we're not saying those aren't equally important to start pursuing. So in some sense, I will also say the collaborator who was the lead on our clinical trial Dr. Joanne Vidal-Jove, he had treated a lot of patients with liver and pancreatic tumors with a thermal version of focus ultrasound, so using it to kill it. So we had a clinician who had experience with liver who knew how we could potentially use ultrasound to target, but at the same time, saw the limitations of using thermal ablation for that indication. So both him as well as the interventional radiology team at University of Wisconsin who do a lot with microwave ablation in the liver. So Fred Lee, Tim Zimlewicz, the rest of their team. So we had kind of this like growing body that we thought we could be successful in starting in the liver rather than starting somewhere that's maybe brand new that we're kind of starting to get to now.

Yeah, it sounds like you all had multiple reasons that that was the best place to start. I'm curious when we...You run into a clinician who works in brain cancer and then they want you to start there. then, so that's why we have plenty of projects going and hopefully we are going to start pursuing more of these in parallel. Now that we have one or two that are getting to the clinical stage. Now the goal of our team is to really scale this so it's not just one at a time but we can start to develop the technology so that it's not going to be decades before it gets out to all these indications.

Travis

I’m curious what does the what does a prototype look like what all goes into when you're like when you're saying we needed to develop a prototype what is that?

Eli

Yeah, so our current hystotripsy systems that are used clinically, so like the Edison platform developed by Hystasonics, it looks like a lot like an ultrasound imaging cart, right? So you have this cart-based device where instead of just having ultrasound imaging probes off the side, they're modified, a little bit larger and modified with a robotic arm and this large therapy transducer. So this large therapy transducer, looks like a kind of curved transducer that's focusing the sound waves down to a single point. And in the center of that, there's an ultrasound imaging probe.

So this ultrason imaging probe is allowing you to see where you're treating so the clinician can identify the tumor, set some boundaries, and then the robotic arm is gonna uniformly treat some predetermined volume. So it's a robotically guided therapy. So that's kind of the paradigm of our current clinical systems. On the research side, we are also developing surgical devices. So instead of being completely non-invasive, they could go in surgically or endoscopically. So we kind of develop devices that have a range of sizes and end uses for any application. So for instance, when we're talking about treating sarcoma or osteosarcoma, we're moving towards more smaller portable systems that could be used at a bedside and target these superficial tumors. And then with the brain, have systems that our teams at collaborators at the University of Michigan are developing full transcranial systems that are guided by MRI imaging. Our lab here is developing these tiny little hystripsy systems and partner with Jeremy Brown's team in Dalhousie University in Halifax to actually go in through a little burr hole in the skull. So there's a lot of different devices that we're developing that can ultimately optimize this therapy for different applications and the way we deliver the energy. But they all really have the same goal of delivering that kind of cavitation really precisely to the tumor.

 

so that we're only destroying the tumor and preserving healthy tissue around.

Travis

Yeah, that's fascinating. With the non-invasive treatment, if I'm the patient, would I be put to sleep to have that? Or is it something you can stay awake and have it done? How does that work?

Eli

Yeah, that's still, I would say, an open question long term for all of our clinical trials and the clinical work, especially in the liver. You can think of that as an organ that can move, right? So you wanna make sure the patient's stabilized. So they're all currently under general anesthesia. Now, there are indications where we expect that that won't be the case. And maybe even long term, they might not need general anesthesia for treating the liver, but that's a question that'll have to be assessed clinically. When we talk about something like a sarcoma, where it's, let's say on a limb, that potentially could just be a local sedation, outpatient procedures. That's kind of how we're thinking about things like fibroids, breast cancer, variety of applications. But, know, assessing whether there's any pain or sensations during the procedure, how do we target, do we need to control breathing? So it's much different if you're talking about treating the pancreas, kidney, or liver, where the amount of breathing is really gonna affect how the tumor moves versus let's say a bone tumor that's just stuck on the limb, it's easier to envision a case where maybe we don't need the patient under general anesthesia. But those are all, that's a great question that we're gonna have to explore in these next few years, because we'd like this to get out into outpatient settings where you're not requiring anesthesia and that's just a further benefit to the patients and quality of life and also the type of patients that might be able to receive this therapy.

Travis

I was going to ask you does it if it hurts to have the bubbles put in in your skin to kill the tumor? Like can you feel it?

Eli

Yeah, that's again an open question. There's some anecdotal reports that, know, I'll say first from all of our animal studies we've done, if you compare kind of how the animal behavior is compared to like a thermal ablation over the week after treatment, it's indicating that systemically there's not pain after treatment, right? Especially compared to these other therapies. So that's a positive and they seem to be well tolerated. Reports from patients, again, this has to be studied, I would say. more in depth reports from patients, you know, the next day they're going home feeling great, know, few new stories have come out with people jogging the day after their treatment. So again, I think it's very well tolerated. I would hypothesize that the question of pain is gonna be location specific. So I think if you're treating, let's say a bone tumor or a soft tissue tumor in a muscle by a major nerve, that's maybe more likely to cause pain than some of the abdominal organ treatments, but we're gonna have to assess that. We'll have to assess that to determine. I will say, I probably shouldn't say this on a podcast, but I had a colleague of mine, I'm not gonna say where it was, it wasn't at Virginia Tech, so we're good, but somebody asked that question, does hystereptisy feel pain? And they stuck their hand in the bubble cloud and they said, well, I definitely felt it. And I'm like, don't do that. So I always tell that story to our graduate students of like, This is what we don't do in the lab. We have specific safety protocols. So I think if you just randomly treated your hands where you have all kinds of nerves, it wouldn't feel great. And we'll have to build there. I don't know the answer.

Travis

I don't think that you're supposed to put yourself in the, I think that's how the Incredible Hulk got in his situation. So.

Eli

Well, but we always talk about no radiation, hopefully we're not creating hulks, but either way, definitely don't ablate yourself.

Travis

Yeah, that's true. That's very, true. You know, a lot of times I ask people what gives them hope in their space, but it seems pretty clear in this space with you. This sounds very hopeful.

Eli

Yeah, I can answer that maybe from a different angle. I think what gives me the most hope is watching the process, right? So we obviously have a lot of hope in the therapy, but seeing the amount of people with different expertise that have to be a part of this, not just in academia, not just in clinical medicine, but industry. We work very closely with the Focus Ultrasound Foundation, which is a nonprofit that has helped fund a lot of this work. And so seeing... you know, our engineering students, working with medical students, working with students within more translational biology, medicine, health, veterinary students, having industry partners. And now we have this global program that we're trying to start in Malawi to really show we can develop technologies globally, not just treat tumors everywhere in the body, but really everywhere in the world and develop this technology in a more low cost way for patients in low and middle income countries. So. But I think what gives me the most hope is seeing this really transdisciplinary group of people coming together. And I have this theory, this is more a hypothesis, but I have a hypothesis that this technology itself fosters collaboration. Just because the nature of it, because it requires, it can't be developed by any single discipline. And so the nature of the therapy is it does break down these borders between traditional scientific or medical disciplines in a way that's really exciting. I'm just kind of an observer of this process and seeing everybody being brought in together. really does give you hope and it's an exciting place to be in addition to what the final end product might be. Just the way this is done is really a privilege to be a part of.

Travis

Where do you foresee or hope that this goes in the next five, 10 years?

Eli

So I would say in the next five to 10 years, my hope is that we can see this. One, for the indications that get into the clinic, I hope that we can develop this and get long-term patient data and really show efficacy and improvement in lifespan as well as quality of life for patients. So that would be number one, is really establishing the role for this in this clinical spectrum and make it standard of care for patients hopefully replace things like radiation, certain ablative procedures, as well as surgery and see the combination therapies start to pan out and have a deeper understanding of which patients, even within the applications that were already given to the clinic, should be receiving hystereptisy. In parallel to that, I would really like to see, and this is something our team's taking very seriously, it's like how do we develop our lab in a way that we can...bridge this gap, we like to say we develop a bench to kennel to bedside paradigm where we're going into our veterinary patients and into humans, but we would like to have this as a frontline therapy for dogs with various tumors, for humans, but how do we get this into more indications safely and effectively and then to patients throughout the world? So I would like to see more indications within that five to 10 year span see us get there. And one of the ways we, and this includes, you we have a big partnership with pediatric hospitals in Children's National has a formal partnership with Virginia Tech now. Dr. Fred Wu, who's my close partner, he just was hired into a role here. He's a radiation oncologist by training, but he was just hired into a role at Virginia Tech jointly with Children's National. So how do we get this for, let's say, pediatric patients that have a significant need, but maybe there's not the same business model to develop this technology for those indications. It's like, that's where we're trying to build this team together that we can get it out for them. So I would like to see even indications that maybe aren't as high a profile in terms of number of patients. I'd like to see this therapy where it can make an impact, get to patients sooner rather than later.

Travis

That's awesome. How do you remember all these people's names?

Eli

I got a sign behind my computer here. Well, thankfully having a name like mine, it actually makes life easy because if I do mess up anybody's name, people are less likely to criticize me if I pronounce something wrong. So I keep that in my back pocket as a comfort.

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Travis

And thanks to Eli for talking to us about his work using Focus ultrasound therapy to treat liver cancer and perhaps even more forms of cancer and maybe even other illnesses down the road. If you or someone you know would make for a great curious conversation, email me at traviskw at bt.edu. I'm Travis Williams and this has been Virginia Tech's Curious Conversations.

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