The Blood Brain Barrier Conundrum

Until only recently, treating Glioblastoma brain cancer with chemotherapy has not been achievable due to the blood brain barrier.  In today’s Bindwaves episode, Dr. Michael Canney walks us through how Carthera developed a revolutionary method to deliver therapeutics to the brain utilizing an ultrasound system.  It is well known that the survival rate for Glioblastoma is 1 to 2 years.  Surgery tends to be the primary means to combat this horrible disease.  To improve these odds, an ultrasound implant is placed in the brain after the surgeon removes the tumor.  This implant, or mesh, contains an ultrasound transducer, which when activated during chemo treatments, disrupts the blood brain barrier thus allowing therapeutics to attach to the cancer cells.   Join us as Dr. Canney eloquently discusses the history of this treatment, Phase 1 and Phase 2 results, and their hopes for the Phase 3 trial. 

Transcript

0:11

Opinions shared by the guests of the show are their own and do not necessarily represent the views of the hosts bindwaves or the Brain Injury Network. This podcast is for informational purposes only, and it's not a substitute for professional medical advice, the diagnosis or treatment. Always seek the advice of a healthcare provider with any questions you may have regarding a medical condition. Thank you.

Carrie: 0:39

Hi, I'm Carrie, a stroke survivor and a member of BIND, and today we're gonna welcome Dr. Michael Canney. He is the Chief Scientific Officer at Carthera. I dunno if I said that right. He'll correct me in a minute. A med tech company driving innovative advances in brain cancer treatment. His work fo focuses on developing new therapies for. Glioblastoma neuro-oncology and neuro-degenerative diseases with over 50 peer reviewed pu publications and a strong commitment to academic collaboration. Michael brings a valuable perspective on improving patient output. So I know I just said all that to introduce you, but how about in your own words, you kind of tell us a little about you better and maybe say all the words correctly.

Michael: 1:26

Yeah, we can start again. Yeah, so the name of the company is Carthera Carthera. Um, and we're a French med tech company, uh, with some US presence. Obviously I'm based here in Denver, Colorado. Um, and we're developing, uh, an ultrasound system for delivering drugs to the brain. we'll talk a little bit more about today. I.

Carrie: 1:46

Okay. Sounds exciting. Okay, so, um, just to get started, so what made you decide to. Get into the brain world, or even maybe more specifically brain cancer research. That's kind of a unique field in my opinion. I don't know, maybe not.

Michael: 2:08

It is. Yeah, I ca I came about it a a little bit through, through a different route, which is that I, I did my research, um, as part of my doc. In therapeutic ultrasound, which is using, you know, ultrasound in new ways, not just for imaging, um, but for, for therapy. And that can be, uh, a lot of different things are being explored with ultrasound, uh, from using it as a replacement for surgery for actually destroying tissue, uh, to drug delivery, which we're gonna talk about today. And, and drug delivery is something that's been explored at least for the brain using ultrasound for about 20 years. I got involved in a project, uh, while I was doing a postdoc in France with a French neurosurgeon, NA, named Alexander Pontier, who had the idea for the system. Uh, uh, this ultrasound system that we've developed, which is an ultrasound implant that's, that's placed to help, uh, help with drug delivery for, for things like brain cancer.

Carrie: 3:03

Interesting. Okay, now let's, I mean, that's, when we say brain cancer, I know most people just think very generic brain cancer. So for myself and for the listeners, I mean, I know a lot I. Not a lot. I know a little bit about a lot of things, especially when it comes to the brain, you know, being brain injured myself. But, um, so like how many different types of brain cancer are there? Because I mean, I know you're focusing mainly on glioblastoma. I never say it right, but, um.

Michael: 3:34

Yeah, we're, we're focused on, you know, these types of primary brain tumors. You, you can divide up brain tumors into primary and then secondary brain tumors, which would be a brain tumor. Say like you have breast cancer and you have metastasis that goes to the brain. that would be a, you know, a secondary, uh, a brain tumor. But we're really focused on these primary brain tumors called glioblastoma. and here in the US they affect, you know, around 10,000 people a year. and it's a very aggressive. Tumor. It's the most aggressive, uh, uh, brain tumor in that, you know, there's very few treatment options and, and once a patient gets a glioblastoma, their survival is, is fairly short. It's, it's on the order of one or two years.

Carrie: 4:14

Yeah. So, okay. That, so I know, um, we partner with a group here in North Texas area called Gray Matters. They are a gray, or they are a brain cancer support group. So we kind of collaborate with them to do stuff. You know, we're all different kinds of brain injury survivors here, but we do have some with tumors and some cancer. And then, you know, the typical stroke and traumatic brain injury, all kinds of random things. Um, so I mean, are there specific factors that make. Brain cancer so deadly. I mean, what, why is it, I guess, you know, do we know why it's what it is? Or.

Michael: 4:58

Yeah, there's a lot of reasons that, uh, we, we, we think, but we can just start with the basics. So if you, if you get a glioblastoma, the first thing they'll typically do is surgery. Um, so a neurosurgeon will go in and they'll, they'll try to cut out the tumor just like they would with a different kind of cancer. I. The problem with glioblastomas is typically is that they're infiltrative. And so when the surgeon goes in, they can cut out most of the tumor that they see, at least on the MRI, but we know that they can never really get the whole tumor. And so typically in six, 12 months, you know, sometimes longer in some patients, the tumor will re reoccur because there's still some tumor cells that are infiltrated in the brain, uh, that the surgeon isn't able to resect. and because of that. You know, in these cells that are in kind of infiltrated, in the normal brain, they're protected by something called the blood-brain barrier. And so the blood-brain barrier, uh, really restricts what can get into the brain. And so if you take something like a drug, a therapeutic, uh, and you give it to someone who has one of these brain tumors. Very little of the drug may actually get to the tumor because of the blood-brain barrier, which is really just protecting the brain, you know, from potentially toxic substances and things that could actually injure the brain. But here, when you have a brain tumor, these tumor cells can actually kind of be hidden behind the blood-brain barrier. And so when you give a therapeutic, it may not actually get to those tumor cells.

Carrie: 6:25

Okay, so yeah, I know. Little bit about the brain blood barrier.'cause like I said, someone from Gray Matters came on and he, his wife had that issue. What it, the sur the treatments that she got, I mean, was. A long time ago, but yeah. Um, and she's actually still alive. She's doing well. Um, but it's interesting, some of the treatments that she got were like new at the time and they were like, just do it and let's use it as research. And so I don't remember what it is. You could go back to one of our podcasts and listen to it, but, um, so, um, let's talk I guess then a little bit about this new treatment technique.'cause. Like, I mean, first of all, let's go back to ultrasound'cause that's very interesting to me.'cause Yeah. You know, when you think ultrasound, you think, first off, you think babies gonna ultrasound a baby? I, I'm, I'm still trying to get the concept of how an ultrasound delivers medicine, I guess.'cause you know, that's unique.

Michael: 7:22

Yeah. So I mean, ultrasound can do a lot of things and so, uh, you know, we use it for imaging that's, that's modality obviously that's been studied for, for decades and decades and decades. But the therapeutic uses have also been studied for a long time. Um, you can imagine, I mean, if you just turn up the power on your ultrasound system, you may actually, you can actually heat the tissue'cause you actually get enough energy in there. You wanna avoid that when you're doing imaging, but if you're doing a therapy, you may actually want to heat the tissue and kill it. So. that's a therapeutic mechanism that you can use with ultrasound. here with, uh, drug delivery, uh, what we do is we actually couple the ultrasound with a microbubble. And so when we do our therapy, uh, and our therapy is an ultrasound implant that gets placed, uh, you know, replacing the skull bone when a patient gets a tumor resection, we were talking about surgeon goes in and cuts out the tumor and places this ultrasound implant. When they get the system activated though, when they get a normal chemo or their drug therapy that might follow the surgery, uh, the patient gets, uh, the device activated at the same time as they get a microbubble, uh, agent that gets administered. So you can think of like a bubble that's actually going through, uh, your blood vessels and these bubbles can actually respond to the ultrasound and vibrate in response to the ultrasound. Actually this mechanical kind of interaction between this bubble and the vessel wall is what can actually disrupt the blood brain barrier. And so we use this kind of a synergy between the ultrasound and these microbubbles that we're giving to disrupt the blood brain barrier.

Carrie: 8:54

Okay. That's, yeah, that's, um, okay. And so how new is this treatment? I mean, are y'all still in the study phase or?

Michael: 9:06

So it's, it's, it's interesting question because, um, they've been looking at this kind of technology, uh, for over 20 years, about 25 years. First paper came out in 2001 by this researcher named CLA Henin. Uh, that was really a pioneer in the field. And since then, uh, there's been a lot of engineering developments to bring it to human patients. And one of the big issues in bringing this kind of therapy, uh, to the brain is actually the skull bone. So when you have the skull and you try to give ultrasound, that will actually absorb most of the ultrasound energy. And so you have some issues in applying ultrasound in a safe way to the brain, uh, when, when you try to use it for something like this. Um, so there's a lot of companies working on overcoming that and sending ultrasound through the skull safely. Our company is a little bit different in that it was founded by a neurosurgeon who said, I'm gonna have this neurosurgical procedure, and at the end of the procedure I'm just gonna place an ultrasound device in the bone window that I've already opened for the surgery. so we place the ultrasound device at the end of this and then we can use it during each, uh, drug drug session. When basically a patient comes in for a chemotherapy, they can get the blood-brain barrier. Uh, disrupted at the same time as they get a normal, uh, drug therapy.

Carrie: 10:24

Okay. Interesting. And so thinking about that makes me wonder, I mean, is this a viable option for everyone that has this type of brain tumor, or is there some that maybe don't qualify?

Michael: 10:40

So going back, yeah, sorry I didn't respond to your full question, but going back to, to the human clinical trials as, um, they started, you know, the, some of this research in the early two thousands, we, we, we, and, and some others treated the first patients around 2014. That with this, this was the first human trials, uh, with our system. And since then, uh, we've run a bunch of phase one two trials and we've recently initiated a phase three trial. So this is still an investigational, uh, device for treating, uh, glioblastoma. And we're in a phase three clinical trial in the US and, and Europe that we hope to finish recruitment in, uh, by the end of next year. the patients that we're treating, you're asking about specific patient populations. Right now in our phase three trial, we're treating patients that have had recurrence of their tumor. So they've already had this initial surgery and, uh, initial chemotherapy, and they've had a recurrence. So the tumor has regrown and then they can come on our trial. But we're actually looking at using our system. in all kinds of patients, in patients who are just diagnosed with the disease and in patients who recur, uh, and, and, and looking at different therapies that can be coupled in those different stages of the disease.

Carrie: 11:50

Okay, so you are still in the trial testing phases of everything. Okay. And I mean, it sounds silly, but I guess your pre preliminary results are looking fairly well, fairly good. I dunno the proper way to say that.

Michael: 12:05

So we published two papers the last couple years from some phase two trials that we did. Um, with different drug therapies. And so, uh, the, the drug that we're advancing with right now in our phase three is a drug called carboplatin, which is an older, uh, chemotherapy drug that doesn't really cross the blood-brain barrier well, but that has shown some efficacy in glioblastoma. And so we really think if we can improve the penetration of this drug, we can really increase the efficacy, uh, of the drug. And so we published this article in Nature Communications. last year, uh, that showed our phase two results, uh, showing, you know, an improved survival in, in a small cohort of patients who had received this therapy. And that's what led us to initiate this phase three trial.

Carrie: 12:49

Okay. And I mean, I'm imagining. I mean, the brain's not that big. Everything up there is not that big. So I'm assuming this implant that you put in is teeny tiny. I mean, how, I mean, I don't know. I'm just like, we occasionally watch, but we just watched a documentary and I don't remember the neurosurgeon neurosurgeon's name, but there's a new neurosurgeon documentary on net Netflix that we just watched, a brain tumor removal. Interesting. I'm trying not to make my faces that I made when I watched the video, but, um, you know, I think about implants and I always, you know, wonder like, how big is that? And do you, what are the risks, I guess, involved with implanting something into the brain? I mean, I know there's other things that get implanted into the brain. I know it's not crazy to think about. It is to me, but.

Michael: 13:49

Yeah, I mean, I actually think it's gonna be more and more common. I think we see this, you know, companies like Neuralink and different brain computer interface companies. You know, in my opinion, I think brain implants probably become a lot more common as, as we advance, you know, across different indications, maybe even things like stroke, which you mentioned. Uh, but yeah, in, in terms of our implant. Uh, you know, we have this device which is about six by six centimeters, and so it's really sized to fit, uh, you know, a normalized bone flap a surgeon would open up anyways, you know, to access the brain

Carrie: 14:25

Okay. Interesting. So, and can you feel it on your head when you touch it? All right. Goes under the bone.

Michael: 14:35

Um, yeah, so you talked about the side effects. I mean, you know, any brain tumor surgery has some risk of infection. We haven't necessarily seen a higher risk of infection, uh, from placing our device versus just putting back, uh, the other bone flap. But obviously this is something that we're, we're indeed looking at in our phase three trial. Uh, whether there are any other. Risk. But so far, you know, we've seen very minimal, uh, side effects from placing this device. Uh, a lot of patients have kept it for years, not had any issues with it, and, and it really is not directly in contact with the brain. So you still have this protective layer of the dur matter, which is covering the brain actually in this device rests, um, you know, outside the dura matter. So it's not directly in contact, uh, with the brain. It's really just, uh, replacing the skull bone that was there. And then sitting on the dura matter. And so, and the device that, you know, we've, we've made is, is made of this, um, uh, mesh. And so this, this mesh is something that a neurosurgeon would typically use if they had to fill in, you know, a bone defect in a patient. So they're very used to actually placing this kind of device and just under the mesh, um, we have these ultrasound transducers that are connected to it.

Carrie: 15:47

Okay, great. I'm gonna take a quick little break and just remind our listeners that while you're listening, and go ahead and click that like button, click that share button, click that notify button so that you can get all the other episodes that we have going on. And then now let's see if I can remember what I was gonna ask after that. Um, oh, and so that device where it's sitting is not. It's on the outside of the blood-brain barrier, but near the blood-brain barrier. Would that be correct? Am I getting.

Michael: 16:20

Yeah. Yeah. So you're getting at something. So ultrasound has a pretty good penetration, and so the, the frequency that we're using is a one megahertz. And so at this frequency, um, we get disruption in the blood brainin barrier up to about six or seven centimeters. I. So ultrasound can penetrate pretty deeply, you know, way you don't necessarily need the ultrasound, like you said, just sitting right on the blood vessel to disrupt it. Yeah. It's one of the advantages of ultrasound versus, you know, some other modalities of energy is that you can actually have it at, at quite a, quite a distance and still have a, a therapeutic effect in this case.

Carrie: 16:57

And I'm not gonna just guess at what you're hoping to achieve through this work. I want you to let me, like, like what's the ultimate goal? What's the, maybe short term versus long term? What, how, what's the, what are you looking to achieve?

Michael: 17:16

Yeah, so this trial is a, is a phase three clinical trial that we're running right now. The goal of a phase three trial is really to, we're randomizing patients, and so patients get randomized against the standard of care that they would normally get if they weren't in a clinical trial. And then they, some pa, you know, half the patients get randomized into getting our device in combination with this, um, carboplatin chemotherapy, which is what we're using. And the ultimate goal of this phase three trial is to show that we can extend survival for patients that are getting our device. And so, you know, this initial trial, if we can significantly improve survival outcomes for these patients with recurrent glioblastoma, I think that's a first step. And that would show technology of disrupting the blood-brain barrier, increasing drug concentrations, uh, really has an effect on the tumor growth. And, and, and, you know, slows down the tumor growth and maybe stops it in patients, uh, to extend survival. after that, that's really a first step and we're looking at a lot of different therapies that could be coupled with the device. And so. Carboplatin that we're using right now is really just a first step. we're also looking at things like immunotherapies. We're looking at other drugs that could be used. And so eventually what I could imagine is a patient may get diagnosed with the disease, they may get the implant right up front when they get diagnosed with the disease, and then we may eventually be able to follow them as they get different rounds of different therapeutics. Uh, so that, you know, all these drugs could actually be increased in the brain, uh, by disrupting the blood brain barrier. I.

Carrie: 18:51

Okay, cool. Um, I'm trying to think if I have any more questions about that. It's, the brain is so amazing to me what it can and what it does and how it can rejuvenate itself and all the crazy things. Um, so what would you say is one of the most rewarding things about your job?

Michael: 19:16

Uh, you know, I think getting, being able to do something that has an impact, uh, this is. A disease that really has a high unmet need. There's been a lot of failed clinical trials over the past several decades. you know, and we're not just developing something that's kind of like a small improvement, I think on, on some medical technology that exists already. This is actually kind of a new, brand new field, uh, still I think has a huge potential, not just in glioblastoma, but it. Other diseases as well that we're looking at. So, you know, this group's looking at Alzheimer's, I think Parkinson's, uh, a ALS. And so, you know, the therapeutic potential is much even beyond this indication. Okay.

Carrie: 19:58

Okay. Yeah, that was gonna be one of my other questions. Do you see this being used in other areas? And so, yeah, it sounds like hopefully that will lead to more trials and other needs and go from there. So.

Michael: 20:11

Yeah. Yeah. In fact, yeah, I mean, you know, everyone working in the brain area treating no matter what brain disease is struggling with this because you can try to engineer drugs that cross the blood-brain barrier. Um, you can try to use small. Basically very small size drugs sometimes cross, but you know, if you just limit yourself to these things, you really, you know, have a very small tool toolbox of things that you can use against these brain diseases. And so once you can expand that, you open up a lot more possibilities in terms of what's possible. I. On.

Carrie: 20:43

Okay, and now I'm gonna ask a more generic question. That's kind of a question that I, again, I'm relating back to us as brain injuries now, and I know I've asked this question. I know the answer, but just in case we got new listeners. So just because you have brain cancer and you have a tumor removed or partially removed, and you're going through this treatment, that does not necessarily mean you have a brain injury. I mean, it could lead to a brain injury, but not everybody that has a brain tumor and has a brain tumor removal ends up in the brain injury camp. Does that make sense, what I'm trying to say?

Michael: 21:26

No, you're exactly right. I mean, so, so usually, you know, a surgeon when they go in and they do surgery, you know, their goal is to resect as much as possible without causing any harm to the patient. So you don't wanna affect a

Carrie: 21:39

Right.

Michael: 21:40

quality of life. And so, you know, I was just at a surgery last week, for example, it was an awake craniotomy, so they'll actually. Do brain surgery when a patient is awake and they'll test functional regions while the surgeon is, know, measuring to see, really make sure that they're not gonna have any functional impairments in the patients. And that's pretty common for these kinds of surgeries that a surgeon would do that. you know, that being said, there are cases where a patient does wake up and the surgeon. Potentially has touched something that they shouldn't have or, or there are sometimes side effects that happen. But, um, you know, for the good surgeons who are, who are being careful, I, I, I think, I don't know what the percentage is exactly for it to, you know, uh, this, these kinds of patients. But generally, I mean, we see the patients after surgery and they're doing, they're doing well.

Carrie: 22:29

Yeah, that's interesting because the, the. Documentary I was telling you about that the guy was awake for that and that was just crazy. You know, he's like, okay, tell me if these musics are different. And so like, yeah, they were asking him questions all throughout and having him do different things. So, but yeah. Um, and then just again, and what is one thing that maybe you would like our listeners to know about? I dunno. Brain cancer in general are ggl geo, is it glioblastoma or gpls? Stoma. I think I'm saying it wrong,

Michael: 23:03

Glio Glio.

Carrie: 23:04

glio. Okay. Um, what is like one major thing that you would like listeners to know? Like maybe they don't know, like what could they find out about? They don't know they have it, but then. It shows up.'cause I assume that's kind of what happens, right? You don't always know you have brain cancer.

Michael: 23:28

Yeah, I mean these, these kinds of tumors show up. I mean, the, the age demographic tends to be from. 30 to, you know, 70, 80. I mean, they, they, they show up across all ages. Um, and so I think, I think, uh, most people seem to know someone, even though it's a pretty rare tumor, most people have somehow encountered this, you know, some, uh, know someone or, or a friend of a friend or something that has had a glioblastoma. Uh, every time we mention it, um. But getting back, let's see. Your question was, uh,

Carrie: 24:04

Like what?

Michael: 24:05

things,

Carrie: 24:05

Something that you wanna make sure that people, just the general public, that maybe don't really understand something that you want them to know about like how to. To find it or be prepared or react or, you know what I mean? Like I, we know there's stroke signs to look out for. We know there's signs for heart attacks. Is there something that maybe.

Michael: 24:30

un unfortunately, I think for a tumor like this, there's very little, uh, most patients may have a seizure. Or, uh, you know, headaches or something. They typically have a neurological symptom that's basically caused by the tumor growing. that triggers them going to the hospital and getting an MRI, uh, to, to, to where they actually learn that they have this, this tumor. they typically also need to do. You know, a biopsy, they can be pretty sure, but, but until they go in and, and actually take out the tissue, they're not always certain that a patient actually has actually this kind of, uh, glioblastoma because there are brain tumors that are less aggressive, uh, that that can, that can form and, and look similar. So that's also possible.

Carrie: 25:16

Okay. Well Michael, thank you so much for joining us today. Uh, this is also interesting and maybe let's circle back around. Next year after you're done with the trials and let's see where you are and get an update from you, that would be pretty exciting. So, but we wanna thank you. Thank you again for being here.

Michael: 25:36

Yeah. Thank you so much for having me on. And, you know, if any patients wanna learn more about this trial, uh, we do have a website, it's Sono bird.eu is the website for the trial. And we're, the name of the company is Carthera, so Carthera.eu is the company if they wanna

Carrie: 25:50

Okay. And we'll, we'll make sure that we spell it correctly in our description. And, um, links don't really work in Instagram, but if you have an Instagram. Um, if you'll send that email that to me, then we'll make sure we tag you on our Instagram story so that people think and find you that way. Um, but yeah, we'll, we'll get that figured out. We'll make sure we get people to you. And then again, I wanna thank all of our listeners for listening. Again, if you wanna contact us, I know you get tired of hearing it, but our email is bindwaves@thebind.org. I almost said.com. And you can follow us on Instagram at. symbol@bindwaves, and our website, thebind.org/bindwaves. So don't forget again to click the like button, the share button to notify that if you wanna watch us on YouTube. But we can find us on all your favorite platforms. So wherever you listen to podcasts is where you'll find us and just keep listening and we'll see you next time. Until, until then, have a great day.

Cohosts: 26:48

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