My first clinical Trial: 5-ALA & Glioblastoma re-irradiation

Speaker A: Hi, everyone. It's Guy Spier here. And for the first time, I'm not interviewing somebody or being interviewed about somebody about investing. I'm interviewing two doctors. The two doctors are in the university clinic of Minster, where they spent, uh. Well, they live there and work there, but I spent a month in hospital doing a special treatment. And, uh, my introduction is just that I am blown away by the minute you step out of investing. How? Uh, there are extraordinary people doing extraordinary things that you wouldn't know about if you didn't step into a different universe, the universe of medicine. And so I just want to shine a spotlight on them. And we have a little agenda here. And so enough of me. And I guess that what we agreed to is that my journey. But. But you. You maybe. Maybe Professor Mutter. And just to be clear, I was, uh, the patient of these two fine doctors and researchers for a month, but we're. No, I'm no longer their patient. I just did a study. So I'm going to get, uh, Dr. Mutter to go first, and I guess, uh, you can introduce yourself, and then you will, uh. I don't know, you'll talk about what you do. Maybe you'll talk about me from a slightly medical perspective. Not too much, because it's for a general audience. Go ahead, Dr. Mutter.

Speaker B: All right. Thank you very much for giving us this chance to, uh, to speak here about all these things that are on the agenda. So, my name is Michael Mutter. I'm a neurosurgeon, attending neurosurgeon here at the Universal Medical Center. Um, neurosurgery is a surgical specialty, you know, dealing with all sorts of diseases and problems around the skull, the brain, the spine, and the nerves around the body. And I'm Myself, I'm specializing on brain tumors, um, and the surgical part of brain tumors and studies around that we're doing. Um, I, uh, was trained, and I am still working under the supervision of Professor Walter Stuma, who's my mentor. And he invented some things and introduced them into the field. He kind of pioneered some, um, some aspects of neurosurgery, um, that I'm trying to continue now in my work. Um, so academically as well as clinically, I'm dealing with brain tumors. And that's how we met Dr.

Speaker A: Mutter. Or maybe I should call you. I don't know if it's okay to go to first names.

Speaker B: Sure, yeah.

Speaker A: We're half in Switzerland, we're half in Germany, you know. But, um. Uh. Do you regret not peering into my brain? Do you think it would have been a good brain to look at. Or they're all the same.

Speaker B: No, they're not all the same. Everyone's a little different.

Speaker C: So, um.

Speaker B: Yeah, I would have loved to do that as well, but someone else did that. But, um, we got together as we have a certain portfolio on. On brain tumor, uh, trials running that we're running here in Munster. And that's how we got into touch.

Speaker A: So, uh. Uh, Dr. Pepper, who I know better, really, because I saw you, like, on a regular basis except when you were in another clinic. And I'm blown away because these people are half my age and they're. Anyway, so go ahead. Why don't you introduce yourself, Dr. Pepper. And I don't know. I'm on last names. What can I say?

Speaker C: Uh, yes, thank you very much. I very, uh. Much appreciate the, uh, chance to talk here about the treatment of, um. Yeah, brain tumors from a radiation oncologist's perspective as well. So I'm a radiation oncologist at the University Hospital of Munster for, uh, seven years now. And, um. My story basically is that I've, uh, originally worked with patients, uh, with Hodgkin's, uh, lymphoma primarily, and wrote my thesis about that. But, um, during my work here in the clinic, uh, under the supervision of Professor Eich, which is the head of our department, uh, I, um. More. More developed an interest into the treatment of, uh, cerebral tumors. And, um. This is how I, yeah, came into contact, uh, with more and more patients with, uh, glioblastoma, which is the most common, um, malignant brain tumor in adults. And, uh. It was in, uh, 20, uh, 23 when, uh. 20, 22. Turning 2023 when professor, uh. Stummer, the head of the Department of Neurosurgery, uh, approached professor, uh. Regarding the, um. Uh. The initiation of a trial. And, uh. Yeah, professor, uh. Asked for someone to. To be a part of this trial, uh, from. From a doctor's, um, perspective. And I volunteered and this is how I came into the trial. And, uh, since then I've been very much working on all different kinds of, uh. Uh, aspects of the treatment of, uh, glioblastoma from a radiation, um, oncologist's point of view, which has been, uh, developing over the last 20 years quite a bit. And it's a very, very interesting field to be working in.

Speaker A: So, uh. Uh, thank you, uh, Dr. Pepper. Or Nicholas. So, um, if I go back to you and I'm just going to go with last names, what can I say? It's just. I Don't know. I mean, I'm German enough to want to do that, but you can always call me Guy. But, um. So, uh, the reason why I came in contact with them is that unfortunately for me, uh, the first line of, um, treatment, which is called the Stutt protocol, did not work or did not work very well. I had, uh, two recurrences. And the, uh. My doctor, or one of my doctors at the time, uh, who knew the German landscape very, very well, said this is a good trial for you to be on. Uh, and, uh, it may help, but, uh, uh, Dr. Mutter, why don't you first explain what Gliolan or, um, 5 Ala dye is and how you use it in surgery.

Speaker B: Yeah, sure. So, um, the problem with brain tumors is that sometimes they're. They very much look alike. The brain itself or the diseased brain. And, um, there are certain tools that we use as surgeons to visualize the tumor. It is with our own eyes through the surgical microscope or the, uh, haptical feedback we get with our instruments. But sometimes it's, uh, it's. It's very difficult. And then additional tools come into play. And one of those is, uh, fluorescence guided surgery with, uh, 5 ala. Um, it's called 5amino alevolenic acid. It is, uh, something that is not artificial. It's, um, one or two may know it from biology class. It's a degradation metabolite of, um, the red blood cells, in fact. So it's. It's not something artificial, but you can, you can administer it, you can, you can drink it as a solution. And then it acute accumulates all around the body and with the brain tumor cells, it doesn't get pushed out of the brain tumor cells, so it accumulates inside, um, the tumor cells as well as several other cell types that are necessary for tumor growth. Um, and so then you can use light of certain wavelength, which you can just put a filter in your surgical microscope. And then, um, you have the tumor illuminated so it gives you a contrast. It shines in sample. It shines, uh, sort of, ah, lava violet, um, pink. It gives different shades of color, uh, depending on the cell density of the tumor. And so you can easily visualize it and make sure that you can resect, uh, the part of the tumor that you want to resect, and that is, um, that part that takes up the MRI contrast. We know that, you know, from your scans, you're. You're getting scans regularly and um, tumors, um, like glioblastoma, they. They light up in this contrast, and that's that's the stuff that we want to take out. And this gliolan. This fluorescence guided surgery or resection helps us very much with uh, with doing so and even going beyond.

Speaker A: Yeah. Uh, just briefly. Uh, that's not the only thing. I mean you have to take care that you don't cut out parts of my brain or somebody's brain that actually you may need after your surgery. Yeah.

Speaker B: Yeah.

Speaker A: So you may have situations where you are you. The 5 ala dye lights up. But you have to be sensitive to other. Other uh, factors which don't allow you to take it out or you have to be very careful. And I know that you have with in the surgery you have somebody who's just responsible for checking uh, what is it called, um, uh, potentials of different parts of the brain to make sure that they're not being used for somebody. Something else. Can you just go into that for a second?

Speaker C: Sure.

Speaker B: So the problem is like with many other organs inside the human body, that most of it is of function. Um, and that's particularly true for. Particularly true in the brain. As most of the brain is functioning. Is it for motor responses or for vision or uh, for speech? And we have different modes of taking uh, care that uh. This doesn't get injured or we get pre. Alerted during surgery that we are uh, approximating um, a certain very sensible part of the brain. And uh. This is why for almost every surgery we have an electrophysiologist with us. Um and we can do certain tests while you're uh, under uh, general anesthesia. And we. For. For certain um, functions that we want to test such as for speech, we need the patient's feedback. So we have certain patients that are awake during surgery. It's uh, a. It's a very established protocol to operate on patients being awake for uh. Especially for checking for speech problems, uh, and language as well. That's, that's been done all around the. All around the world nowadays. Um and the patient only have a. A local anesthesia of the skull and um, the meninges or the. The. The skin on the brain. That's sensible. The brain itself doesn't feel any pain. So um, with that you can check with a. With certain um, electrodes you can sort of numb the brain for a very little time and then give the patient the task to acc. Such as reading or pointing at numbers or calculating or something. And if we see the patients are stumbling then we know that part of the brain is important and we have to leave it there. And that is something that we develop over time during surgery. And then we have to find a so called onco functional balance. So we have to balance out the function and the oncological benefit that the patient has from resection. And that is a fine line sometimes and takes, Takes uh, a little experience as well. So we can't just take away everything that lights up with uh, a fluorescence. So we um, at the same time we have to think about the function and what it means if we did take this out. So that's basically what we do in brain tubing surgery.

Speaker A: So in case you're interested, um, I could never. If. You know that if I was in your field, I'd be in the direction of Dr. Pepper. I could not do how you do it. I have no idea how. And just for your interest those who are listening, I was not woken up during surgery, uh, for whatever reason. And um, we cannot do a biology course or a neuroanatomy course in an hour and a half or what we have together. But I don't even want to. And uh, I don't even want to get into the discussions that you have before and after surgery. Uh, I just can't imagine. But I'm grateful that in the three surgeries that I had so far, I was not woken up. So, um, but the next thing that happened to me after my first surgery is that I got radiotherapy. Uh, so I, So. So, uh, Dr. Pepper can explain it a lot better than I can. Why don't you explain what I've been through and why I was re. Irradiated?

Speaker C: Yes. So, um, I think, uh, that's a good point. I would just take a step backwards because a lot of listeners might not be familiar with the concept of radiotherapy and radiation oncology as a whole. The main part is that radiotherapy today is a very important cornerstone of oncological treatment in a lot of different, uh, circumstances. And at this point basically goes for all kinds of different tumors. So we're not just talking about brain tumors. We're also talking about tumors of the lung, tumors of the, the breast, the prostate. All the familiar tumors are, um, irradiated, uh, in some kind or another or for, um, in different scenarios. And um, the reason for that is that, um, like Dr. Mutura just previously explained, the surgery alone not enough, so to speak, because you can only take out a certain part of uh, the brain. And we've learned in the last, uh, couple of years that, uh, especially glioblastoma is a disease that, uh, tries to infiltrate the working part of the brain like A network in a way. And um. So radiotherapy has been very established for a long time in the treatment of brain tumors because we most certainly know that for most types of brain tumors after uh surgery itself there are still some cells left uh around the perimeter of the main tumor who can then grow and can uh cause a relapse of the um of the tumor. And with radiotherapy we try to target those cells and try to uh, eliminate those cells. And what we're using for that is uh ionizing radiation, uh mostly in the form of photons and uh, depending on the, on the tumor itself, um and location of the tumor, electrons as well sometimes and uh, photo uh protons are also used in uh, the irradiation of tumors, brain tumors, but also different tumors. And those are types ah of radiation we're using as a local treatment to kill those tumor cells. And uh, for the first line treatment of glablastoma um we use a uh six week course of radiotherapy um, which has been agreed upon uh of based on study data. And in this study data the six week dose of what is cumulative, 60 gray which is the, the uh number so to speak for the radiation uh dose uh has been uh applied because for yeah mostly all the um, most types of radiotherapy we are doing what we are calling a fractioned radiotherapy because if you would apply all the dose, all the dose uh for the radiation at once it would be detrimental for the uh healthy tissue as well. And for us like for the surgeons we have to find a balance between killing the tumor cells but also uh, not harming the normal tissue and the remaining tissue as much as possible. And uh, with this type of fraction radiotherapy we can find a balance between treating the tumor to a degree where it has been ultimately killed and also not harming the normal tissue. So which is, this is why radiotherapy is not done in one session like most surgeries uh are. But normally uh, takes up a lot of time and like you just said a six week course of radiotherapy is the uh, uh yeah, the common treatment for glioblastoma, uh in the first line

Speaker A: and just for what it's worth, um, uh you know, and again this is very surface level knowledge but they have, they have ways of focusing the um, the uh, uh X rays if you like or the radiotherapy in such a way that only the tissue that you need to get irradiated gets irradiated. And it's pretty cool system and they're very expensive machines that you go for. But literally I was there for A month. Uh, but really uh. The treatment was five days a week, um, for ten minutes. And then I. Then I was resting effectively the rest of the day. And I guess, um. That's true of many other kinds of radiotherapy. Not just mine. I guess.

Speaker C: Yes, uh, that's. That's the uh. Most common type of radiotherapy. So it's uh. Very few very short hours, a very, very short treatment for every day of a long period, so to speak. And I completely agree what you just said. So the um. We are able today to focus the uh. X rays on a uh. Certain uh. Area which we call the planning target volume. So it's a. It's the target volume which identified as the um. Area that's been in risk to hold, uh, tumor cells plus a certain uh, margin around this area, uh, just for safety measures, um, as well. And this area is then uh. Irradiated with a dose which has been uh. Prescribed at the beginning of treatment. And regarding the dose for a second course of radiotherapy, we know that we are limited because we can't apply the same dose, uh, like we did in the first time. And this is because for the uh. So once again, if I. If I take a step back for. For the longest time actually people believe that uh. One course of radiotherapy was all the. Was possible and that the second cause of radiotherapy was basically impossible. And it would be too much and too toxic for the. For the brain. Um, because um. Of. Yeah. Um, prior trials which have shown that if you go over a certain dose then the risk for uh, side effects and for necrosis. So uh. The dying of healthy tissue is too. Too big. But we've learned a lot in that regard. And I think it's safe to say that today the second course of radiotherapy has been very close to a standard in the treatment of brain tumors. Uh, and this has basically changed just about 20 years ago when the first reports regarding the first uh. Appearances of reradiation of brain tumors, uh, were published. Interestingly, this is. This is kind of around the same time when uh. Professor Schumer first published about the uh. Yeah, the effects of gliolan in. In uh. One of the most famous uh and prestigious medical papers where he wrote a very, very big article that uh, basically put the gliolan on the map worldwide and has been uh, able to establish that as a local treatment, as a treatment, uh, in neurosurgery. At the same time, the first reports regarding re. Irradiation were also published from uh, colleagues here in Germany, for example, uh.

Speaker B: Um.

Speaker C: Two Very, very famous, uh, colleagues in this regard. Uh, this is Professor Combs and Professor Grosso who are now today the heads of the departments of Radiation Oncology in Munich, um, and at Freiburg, and have been working with the um, Neuro Oncology working group, so the brain tumor specific working group of the German um, Cancer association at that time and have been pioneer, have done pioneering work in that matter and built on that experience had, uh, published larger amounts of patients and were able to show that second course of radiotherapy is doable. It's, it has a low risk for toxicity, has a good safety profile, and it's also uh, more effective than what has been the standard before that, which was just, um, just chemotherapy. Uh, so, yeah, the re. Irradiation has been established, so to speak, in the treatment of uh, brain tumors and in that way.

Speaker A: So, you know, I get to say something that um, just for fun before I go to my next question, which I'm really looking forward to asking, is that, um, you know, first of all, thank you for doing this in English. It's not your mother tongue, you know. And maybe, you know, as we all know here, and you may be aware the audience, um, this was. First of all there are in Minster, which is by the way, as beautiful as Oxford. It's really a lovely place to study. And there, it's a university town. There are many students there. But, um, there are multiple statues of. Professor Rontgen was a German guy who discovered uh, the X rays, I don't know how, 100 years ago, something like that. And I think to this day there is a lot of great. And I don't really know because I'm not, uh, in the field, but there's a lot of great science that is done in Germany that for one reason or another, is not spread quickly or fast enough around the world. And I think to the extent that I can help do that by this podcast, if that happens, then I'll be grateful. But now I get to ask uh, Professor Pepper a question that. So when, when they're in the hospital, I don't know if some of you will have been in a hospital and people like the minute you have a white coat on, especially if you're, uh, a senior doctor, you have calls on your time constantly. I can't believe that neither of your phones has rung actually. But, um, and even as the patient, even as a valuable patient, you know that they have so many other calls on your time. So I know that you've done this once before, but it seems like first of All. It's very beautiful. It's a very elegant idea that the very thing that you do that you explained how, um, the normal cells metabolize the ALA dye, uh, the cancer cells don't. And then there's a mechanism by which they are weakened, uh, and make them more vulnerable to radiotherapy. And I know you could spend two hours on that or three hours. And probably you do when you do lectures. By the way, there's a whole school of medical students, which is right next to the hospital. I was offered to go in. I didn't go in. Maybe next time when I come back, I'll go in and take a look. But, um, now I get to ask the question. And he's committed to my time for a while. So how does that work? And why did it take so long for somebody to actually do a study on it? If you knew about Ala Die, uh, 20 years ago, it seems like it's an obvious idea to do what you're doing now with the study that I'm on. Blast away.

Speaker C: Um, yes.

Speaker A: Good luck.

Speaker C: Thank you. Uh, so, yeah, I mean, uh, it kind of depends. First of all, I want to say, uh, I turned my phone off. That's why I didn't bring it.

Speaker A: Because otherwise these guys are so much in demand, you can't believe. Anyway. Yeah.

Speaker C: Yeah. So, uh, the, um, reason why this kind of took a while is because, uh. Like I talked, um, about before, the re. Uh, irradiation as itself. We had to come accustomed to that at first before we were able to do, uh, further steps and then, uh, try to enhance the treatment and enhancing the treatment is basically the idea which we, uh. Which we were focusing on because, um, like I just said, the. The normal tissue, um, has to be cared for when you're doing radiotherapy, uh, as a whole. And especially when you're doing, uh, re irradiation. Because the normal tissue doesn't forget the prior irradiation. And so what would be the thing that you wish for as a. As a radiation oncologist would be some kind of medicine or something that you can give the patient that lets you achieve more with less radiation dose. So, uh, that's what we call a radio sensitizer. So something that works preferably just in the tumor cells and somehow doesn't affect the normal tissue. And, um, with the five ALA Just, uh. Just touched on that a little bit. That professor, uh, Schumer already 20 years ago published, uh, groundbreaking articles about that. And, uh, at the same time, uh, first reports on RE irradiation surfaced, and then Five years later, bigger uh, reports regarding the RE radiation. But for the next step to happen, it actually kind of took a. Took a while because, um. The connection between the UM5 ALA and the radiotherapy that took uh, a while. And before you can transfer the findings which were then uh, made, um, especially by several working groups in Japan who've been working in this field as well for uh, for a long time, that you can also use radiotherapy to kill tumor cells that have been um, loaded with five ala or the different parts of ALA that uh, actually mediate the. The effect of the five ala. Um, this has been. This took quite a while. And so we actually started developing this trial uh, in Munster six years ago. And Dr. Mutter is actually working um, in the fields, uh, with the five ala, which doesn't only use the radio, doesn't only use radiotherapy, but also what we call photodynamic therapy. So um, the stimulation of tumor, uh, cells who are holding five ala with uh, light of a certain wavelength, which doesn't only show the tumor but also kills it with a uh, laser, so to speak. And the idea um, is for the photodynamic therapy you have to get the laser parts, the diodes the uh, light directly into the tumor. While with radiotherapy you can do it externally and you can just use uh, the linear accelerators and the X rays can penetrate the brain and uh, go into the tumors and have the effect there without having uh, to do a surgery and uh, do a um. Put the patient under anesthesia.

Speaker A: Uh.

Speaker C: But yeah, to put all those pieces together, it really took quite some time. And we're the first ones who are doing a trial, uh, with humans, ah in that regard. So there's been like I, like I said before, a lot of uh, other broad shoulders which we can put our research, um, uh, on, uh, for example the colleagues in Japan who've been uh, doing all those wonderful uh, cell trials and animal trials and have shown that the effect is there and that it's um, also doable with photon irradiation. And uh, based on that we were able to um, produce the trial and then later on open the trial. But before we can really start with the first patient, you have to go through a lot of. A lot of. There's a lot of rules to follow. So you have a lot of rules which you have to follow. And uh. A lot of checks have to be made on certain uh, checklists before you can start with a trial. And um, of course when you're doing a trial with a uh. With something that's a uh, combination of treatments that are done for the first time with human patients. Uh, the safety regards are very uh, very high, which is uh, rightfully so. And uh, the regulations are very, very heavy. And we have to uh, get all the uh, prior security checks first. And that's why it took a long time.

Speaker A: Why. And this is where I get to like. So at this point if um, if uh, Dr. Pepper is doing his rounds, he's had three phone calls and three people have tucked his shoulders and he's in a different thousand different directions that he has to be in. But why do we know that the um. So. So we know that it, it stays in the, in the cancer cells and it gets metabolized in the non cancer cells. But why do we know that it makes any difference to the. Like you, you would want to say that um, the five ALA dye absorbs more of the energy of the um, of the X rays that are coming in. But uh, that depends on maybe the frequency of the radiation and a whole bunch of other things. Uh, why do you. What is the theoretical basis for why that is actually has an effect? I mean maybe, maybe it's like glass. It's just the five ALA dye is just transparent to the uh, to the radio waves, you know.

Speaker C: Yeah. So um, like Dr. Tomito previously said, the 5LA gets metabolized in a different way in the tumor cell. And uh, we have a um, a product of the 5 Ala metabolism which is called PP, uh 9. Protoporphyrin 9. And this uh, accumulates in the tumor cells. And so while the uh, the whole story of the mechanism is still topic of further research, we know so far that uh, the most of the effect of the. What we call radio dynamic therapy. So It's a combination of five Ala, uh, with the radiotherapy, uh, is mediated by the protoporphyrin 9 which is met by the ionizing irradiation and causes reactive oxygen species. So a lot of our cells or most of our cells have oxygen loaded into them. And um, this oxygen can be used as a, as a mediator of cell killing, which is something that also happens with normal radiotherapy, but especially happens for cells which have uh, the five Ala inside of them. And the reactive oxygen species then just. Yeah, basically attack different parts of the cell, of the uh, vital organs of the cell as well. And this causes the cell to die. So that's the theory.

Speaker A: Do you ever get sick of trying to explain that? I mean I imagine that every single person on this study, for example, wants to have some version of that explained to them. Do you ever get sick of explaining to it it. Because at the same time there's a limited. You are in yourself trying to advance the knowledge. There's a certain amount that you know. And then you have to break it down to sort of like simple things for people like me and all the other trial patients to uh, to explain. Is it. Do you get not. Not get sick of it, but do. But it's like you're not. You know what I mean? You're kind of explaining to dumb people in a way. I mean, in the one hand we're patient and we deserve to know. On the other hand, you'll never be able to actually explain what's really going on because it's difficult, you know.

Speaker C: Yeah, yeah. That's the interesting part. Because to, uh, be honest, it's very hard to explain something that hasn't been understood fully as a whole because, um, there's still so much work to be done about the, the effects for clinical trials. You have to have the uh, ground research. You have to have the um, the, the. The models which show the effect. But sometimes the effect and how it actually works. Uh, it's not 100 understood. And uh, for the. At least for me, for five ala and the, the working process, it's. It's the same in a way because we have a lot of information, uh, why it works and how it works. But there's so the, the human body and every human cell is such a complex concept and such a complex specimen that the, the whole story of what happens and for example, why the 5 Ala is uh, metabolized in the way it is metabolized in glioma cells. Differently. There's still much to be learned about.

Speaker A: Yeah, it's, uh. You know, um, I think that one thing that I've learned, and you know about biology in general is that, um, there are many networks. We know about complex. I know about complex adaptive systems. But in, in um, biology, the complex adaptivity happens on multiple different scales. So you have the molecules at a very small scale. You have chemicals interaction outside the cell. You have kind of like different scales of operation. And you can be specialized in only one certain part of this, which is why, for example, maybe this is a nice segue. Uh, I see a doctor, I see two doctors, and your knowledge interfaces a little bit. But then you have all these other ways. I'm trying to understand now a little bit what kind of T cells there are. And then I've learned there's something called an dendritic cell and uh, there are all these other therapies that come in to play. And so why don't we start here? Um, so your study. And maybe you can do just five minutes or less on what a dose escalation trial is and why you do it and why the endpoints are basically just safety. And you didn't go to the next step of looking at, uh, survivability or some other kind of something, uh, that I would prefer that you looked at actually, which is, does it work?

Speaker B: Usual sequences is traditionally in science, and that's scientific etiquette. If you want, um, is that you up with an idea, then you go into the petri dish. So in the lab, that's a wet lab experiment. Then you go into animals. And if that all works out. Because as you said, the complexity is on a multiple levels, um, other than maybe an economy. And there. Plus there's the unknown, as you said. And then that's the reason why you have to go so many steps until you can finally go into an early clinical phase study. That's what this was. Um, and then you first, you focus on is this treatment really, is it safe, Is it safe to go on and treat more patients? And that's the reason why these early, uh, trials and we understand different, um, phases. This is a phase one, two, and then we go into two and then three. So, uh, phase one studies are very early and they concentrate on the endpoint of safety. And that's the primary endpoint. That's how we calculate how many patients we need to answer a question. Um, um, and if that was answered positively and if we get what we were wishing for, then we escalate and then we change the, um, the sample size a little bit. We can treat more patients and then we can go on into. Is, is there a real. Such as with brain tumors? Is there an oncological benefit? Are survival times prolonged? Are there, is there a better quality of life? That's another endpoint which is very important and gets even more important. That has been neglected a little bit in the last decades. But it's becoming more and more important. And obviously it's important how, how people feel with their disease. Um, yeah, that's, that's, that's basically, um, um, what needs to be done on or needs to be said, needs to be answered. Your question, I think. Yeah. And then those escalation, maybe Nicholas, you can go into much more detail. But usually, uh, that's, that's also what we do with other trials that we are running on our side from the Neurosurgical department. If you titrate into something into your cohorts, um, you try to start, if you want to find the dose, you start with a lower dose and you treat a certain cohort and then you can escalate into the next cohort, uh, treating more patients with a higher dose. Um, that's usually how it works. And with this, um, radiodynamic therapy, we start with a couple of times of the drug being administered prior to radiation and then we escalate into more times. We don't escalate the dose itself, but it's the frequency of, of application.

Speaker C: Yes. Correct. So, uh, for, for our trial we chose a, um, basic, what we call a three plus three, um, dose escalation protocol. Uh, I will get on that in a minute. But uh, so the idea is we have to have the 5 Ala inside the tumor cells for it to work and we have a longer period of uh, radiation treatment. Um, like we talked about before, it's been, it's over the course of several weeks actually. And um, so the basic science and the experiences from neurosurgery just apply it one time for, for a surgery, for example. Uh, and we are the first, uh, trial to do multiple applications of uh, 5 ala in this context. And uh, this is why we actually started with um, one application because of the surgery and one further application with the treatment. And then build on that with this, uh, dose escalation, um, study just adding for each cohort, uh, one more application. So the final number of applications will be eight. Uh, we are hoping to reach that this year. And um, how the three plus three dose escalation, uh, module works, uh, it's basically all uh, focused on uh, toxicity of the treatment, uh, and how well, like Dr. Mitcher just said, how well the patients um, are doing with the treatment and if there are any side effects. And we're putting three patients under the same dose level in each cohort. And if they are, if none of them has any side effects, it shows us that it's uh, a well tolerated dose and we move on to the next level. If one patient has a side effect, which we call a major side effect, so something that would tell us to alter the dose, we would then, uh, repeat this cohort. So with the same dose level three, uh, other patients would be treated inside the study. So we would then have six patients. And if one or more patients of the dose level, so two or uh, two patients or more of the dose level, uh, would have side effects that would be considered, uh, too toxic. And the prior dose would be the maximum tolerated dose, which is what we are finding, which is, uh, trying to find in this study. So the maximum tolerated dose is what we're aiming for at the moment.

Speaker A: And for your interest, uh, for the, for the, for the listener's interest. I was on Cohort 6, so I had six, uh, uh, doses of ALA dye. So in my lifetime I've had eight doses. Two in operations and six during the treatment. And uh, other than uh, a little bit of, uh, nausea, which was not pleasant, but it was fine. Uh, um. Uh. But what's interesting to me, and we shouldn't dwell on it, is that I know that in a way, you know, 100% that you wouldn't start doing the trial if you had any doubts as to whether it would be tolerated. You in a way have no doubt, but you still have to go through it. And uh, you know, you would probably, you'd probably give that you could, you could drink it every day for the rest of your life and you wouldn't have that much problems with it because you. Because I didn't realize until this podcast that it's something that it's. That it. It's something that is natural to the body anyway. But, um. And. And another question that I wanted to ask. When I did the ALA dye, I had to. I also took extra, um, oxygen.

Speaker C: Yeah.

Speaker A: And. And some people when I was walking around the hospital, they thought that I had uh, you know, some kind of heart disease or lung disease. And I was like, no, no, no, it's not for that. And so for example, I'd. I'd have this kind of like, uh, feed for oxygen. And then they think that I needed to put it uh, on after the radiation. I was like, no, I don't need to put it on anymore. It's all fine. Do you want to explain what was that was about?

Speaker C: Yeah, that was uh. Like, uh. I previously mentioned shortly that we are, uh, seeing oxygen as a mediator of the cell killing inside the tumor cells. So, uh, this is why uh, patients uh, during the trial also uh, get oxygen prior to the radiation treatment. So just to load up the body with X max as much oxygen saturation as possible for uh, the treatment just to maybe get even a little bit more extra effectiveness out of it. And um. So something I wanted to uh, also um, maybe point out a little bit more is like you said before, we are not focusing too much on the survival part of the. Of the endpoints of the trial. But of course we're looking at the patients and how they are, uh, how they're doing. And if. If we see a potential, uh, benefit when we compare it to. To other trials we did in the past and to uh, other cohorts we've treated. And um, for this kind of trial, it also. I think it's worth to mention that to do such a trial you have to have a, ah, cohort or a group of patients who are as close to the same as they can be. So you can see the results in a. In an optimal way without having too much, uh, different, uh, confounders and uh, some other aspects that might influence the treatment. And um. At the stage of the trial we're at the moment now, it would be very hard to find those patients. And I think the hope for the. For the treatment itself is that it can later on be, um, combined with all sorts of other treatments. Because from. From our perspective, uh, the five ala, like you, like you said before, is very well tolerated and uh, has a. Has little amount of side effects. And uh, the idea and the hope is that it can also be combined with uh, chemotherapy during the radiation treatment and um, with other parts or with other kinds of treatment without having to worry about, um, side effects that ah, are playing off of each other. Right.

Speaker A: So, uh, as you can see, you have to decide whether you want to go into. I mean, in a different world, I would have joined you in your research, but I guess I am joining in your research participation. But, um. So you're doctors, but you're also researchers. Uh, part of your work is to meet with other scientists to find out what's going on in the world, to read papers to encourage people to join you in doing the research and not becoming finance guys like myself. Although you have to know that at least once or TWICE I told Dr. Mutter that if he wants to become a venture capitalist, I'm sure he'd do really well. But, um. Do you want to talk about just how you interact with other scientists who are trying to solve the same problem from a different direction? Uh, that part of your work. Part of your work is just clinical work, but part of your work is research and networking and finding new ideas and um. I don't know if I've given. If it's too broad or, uh. Dr. Mutra is nodding, so go ahead. Yeah, yeah.

Speaker B: I mean, sure. Especially for the. For the field of brain tumors. You. You just have to accept that you are not the only person to treat the patient or to cure the patient. You need a team effort. It's just so necessary because you know, as said, um, the tumor, it. Especially the glioblastoma, it grows inside the normal brain. So you can't just, if you want to heal the patient, take the tumor completely out. You have to, and you have to remove the brain. In fact, nobody wants that, of course. So I have to leave something behind so as take as much as is safe and then the rest needs to be treated as well. That need that, that was left behind, that is done by, by Nicholas and, and his colleagues. And then there are other people that. Specializing on, on chemotherapy or other special treatments that are on the, uh, investigation. And with that, it is so important to talk to other people and think outside the box. Um, and um, that is something that is done all around the world and also on a national level. Here in Germany, we have the German Cancer Society and they have a sub branch for, uh, neuro oncology. So all tumors that are growing along the nervous system, either central or peripheral nervous system. And we meet with radiation oncologists, neurosurgeons, neurologists, neuropathologists, uh, neuroradiologists, uh, trialists and other specialties that we need and also basic science people, uh, that are all necessary to really, uh, that we can all proceed together in this field because we're dealing with a lot of very rare diseases. It's not, uh, lung cancer or, or breast cancer that is, that is, um. It's just, you know, all these. We have so many different cancer types in the brain or that are. That are possible. Um, and that's the reason why we need so many people and bright minds that stick, uh, their heads together to, to really go on and uh, maybe you, you, you. You said that before. Because the first line of treatment after diagnosis, that's pretty much clear what needs to be done. That's in the guidelines. But after that, with the first recurrence, uh, all the guidelines usually say that you have to go on to a trial and we need those trials. We need, we need the science, we need the clinical research, uh, to proceed and really see what, what treatment really works. And that's the reason why research is such a big, uh, part of, of treatment of these brain tumors.

Speaker A: Yeah. So, um, so when were you last. No, you're the last. You in Ravensburg or that's about to happen?

Speaker B: Yeah, it's about to happen. That's, that's the annual meeting of the German Society of Neuro Oncology. It's going to be in, uh, in May in Regensburg.

Speaker C: Yeah.

Speaker A: Did you want to talk about a little Bit. What are you going to do there?

Speaker B: Yeah, so we have a couple of trials here on our side that we're gonna um, that we're gonna report on, uh, as a progress report. And then there are several scientific sessions on all different kinds of treatment. You know, um, especially of interest is molecular, uh, molecular therapy. So all the genetics and the genetic workups and diagnostics, they're getting better and better. And we tried and we're retaining or especially also in cancer medicine in general, we, we will. We find alterations in the genome of the cancer cells that some of them can be um, can be addressed with very special medication. And that's usually quite expensive medication. It's not the usual chemo drug. It is. It is something called targeted therapy. And that is a field that is uh, that is very much up to date. And um, we can um.

Speaker C: Um.

Speaker B: Over decades, you know, there's. There's been so much, ah, so many, so many genes that were found, so many drugs that were developed in. Over the time. And that is something that is definitely of interest right now. And just uh, we need to talk about this. We need to talk about who. Which patient needs to be analyzed, uh, and which drugs are on the market which really, you know, um, find its way into the brain. Because that's a problem. Not all drugs are working inside the brain. Um, only a very few. And that is one of the. One of the biggest problems in fact in neuro oncology that, that we only have a few drugs that we know that are working.

Speaker A: Um, why is it addition that I want. Yeah, go ahead.

Speaker C: This, this uh, list of uh, topics there. What we also will host once again is something uh, that doctor uh, Mutter himself actually developed, which is the curriculum of the German uh, cancer societies branch for neuro oncology, uh, which is especially designed for younger ah, colleagues and for colleagues who are getting to know the field of neuro oncology and the treatment of brain tumors and want to uh, get to know the treatment from all different angles. Because um, for for example, for me I'm a radiation oncologist. I'm just being treated as a radiation or trained as a radiation oncologist, uh, and learning about all the different aspects of uh, radiation oncology for all different types of tumors. But uh, to really understand the treatment and to expand the horizon, it's a very, very good idea to also understand what the other disciplines and the other doctors treating the patients are doing as well. So what Dr. Muta did a few years ago, I think four or five years ago maybe. Yeah, yeah. Ah, he Started, ah, a curriculum for um, all people who are interested and wanted to know how the treatment of tumor patients, uh, works from a neurosurgeon's perspective, from an oncologist's perspective, from a radiation oncologist perspective, uh, from uh, people who are working, uh, in the uh, rehab facilities and from a academic point of view. So all angles of treatment are ah, addressed. And we um, are ah, at the moment hosting those curriculums twice a year for everyone who is interested in the treatment of cancer, uh, of brain cancer patients. It's a very, very uh, interesting, um, program to be joining.

Speaker A: And just again, part of my interest in doing this is that um, for some reason I don't. Maybe you have explanations, it doesn't really matter. But, um, I think that Germany is uh, the most advanced. I know that when it comes to diagnostics and for example, sequencing brain tumors. And it's not just sequencing the uh, DNA itself. There's various different peptides or peptidomes that you can sequence. So it's not how the DNA is, it's how the DNA is expressed in a particular cell or in a particular body. Uh, why is it. Actually, I will ask the question. Why is it that uh, Germany is so far ahead? Is it just that Trump has um, uh, cut funding to uh, to medicine, uh, in the United States or what. What's going on? I mean, Germany used to be the best at this. Uh, Ronkin was a German. Um, is it. Why is Germany so far ahead? And for example, I was in. I was talking to a colleague, a uh, somebody in my family who's a doctor, and he actually said that the best research is being done in Germany. And I don't know why. Maybe I'm just an Anglophile or something. You think that the best research will be done in the US Universities, but it's not the case here?

Speaker B: Well, that's a good question. Uh, not sure if we find the exact answer on this call here, but I um, think back in the days with Odol Virtual and Robert Koch, um, everybody had to learn German because it was the, the language of, of science. I think that was a long time ago. And um, many people moved to, to North America and the US Also for other reasons, obviously. But um, you know, um, there's a lot of activity there and there are so many more Americans than Germans. But um, for. For whatever reason, we, we have a, we have a good environment here. Ah, good research, um, support by, by the government, many open and public grants that you can apply for, for your research and There are certain little nests of, of research, um, especially in southern Germany, um, that work very well and that produce a lot of uh, good results and good research. Um, and the pipeline of you know, going from uh, from basic research into translational research and clinical trials works very well in Germany for whatever reason because we know that the regulatory environment has become very, very strict not only in Germany, also in Europe, which makes you know, conducting a clinical trial ah, a large endeavor and it, it takes so much breath, um, but we're doing it as, and um, for whatever reason it works. I think there's, there may be some historic reasons for this. Uh, but if you know, if, if, if one, one person or one, one leader, one dinosaur starts his work and many, many people are following. I think this is also much about mentorship, um, like in many other fields of human existence. Um, I, I guess that this is one of the biggest drivers.

Speaker A: Yeah, so I, I, yeah, go ahead Nicholas.

Speaker C: I, I, I, I totally agree. I think that uh the um, like just said the mentorship and uh, especially the, the networking aspect of the, and the possibilities we have here, uh in Germany, uh especially like the Neuro Oncology working group, uh, which has been uh, blessed with a lot of, a lot of very, very passionate people who are doing a lot of, of great research. And uh, so the, I think most of the trials that you just mentioned, um, that your colleague also mentioned that ah, are done in Germany, uh um, brought to the light of day by a lot of trials, uh, brought to light of day by the Neuro Oncology working group. And um, we have a lot of very very passionate researchers who have a good hub there to just uh, just bounce ideas of each other and work together and also um, refer patients who are fitting certain trials to one another. And the network that's been uh, woven over Germany in this uh, regard is very, very helpful for that.

Speaker A: And um, so I have, so I will say this because obviously this is primarily an English speaking audience. So if you're thinking about whether you want to participate in a trial in Germany or particularly in university, uh, clinic in Munster, I can highly recommend it. Um, don't think that it's just for Germans. They are very welcoming of people from all over the world and so just consider it if you're thinking about it. But um, my last question to you is before you go back to all your phone calls and all the other things that you have to do is uh, should I think that leave out ah, Ravensburg, but should I attend as an individual, a uh, patient? If you like uh, the Neuro Oncology association meeting in Munster coming up later this year.

Speaker B: Oh, absolutely. I mean we've always. It would be a great honor to have you with us and um, besides your person. Um, I think the whole field is changing a little bit. I mean the people. The Society of Neuro Oncology of Northern America is, Is already um. Is. Is. Is already doing this. That all the um, conferences are open to patients as well. And there are certain workshops that patients can participate. And this whole patient involvement is getting more and more important. And obviously it is important. I mean, um, if I create a trial that is so cumbersome that a patient wouldn't, wouldn't last, uh, the whole trial, it um, doesn't make any sense because. Because I can't, I can't use any of the data. Um, and that's the reason why involvement of patients is so important. And not only in our trials, but also in the whole treatment process. And many. There are other things that I mean we can't change. We can try to change perspectives but um, it's. It's always something different. Is patient has, has his thoughts and, and. And tells us about what he think he or she thinks, um, um, about a trial or about um, a clinical treatment or a sequence of treatments or how they um, are. They're treated and what their wishes are. I think that is very, very important. And uh, I think Munster, uh, um, our conference. So the German Society meets twice a year. The first meeting will be in Regensburg in May. And then in October we're going to have the second meeting in Munster. Um, this is going to be the ah, first conference where we will have a proper patient involvement, you know.

Speaker A: Uh, so, um, just as a complete aside as we kind of wind down this wonderful conversation, I really appreciate you spending the time with me is that I have a friend who's a maths professor and he nearly took a job. I actually took a photograph because there's a new maths building going up or a new maths and physics building. And so he might have gone to Munster, but he came to Zurich University instead. But um, from my perspective, uh, so when I was first diagnosed with what I have, I didn't want to think about the medical side. I was afraid of thinking of the medical side. And um, I think it's from Carl jung. I'm not 100% sure. He said maybe it's a guy called Joseph Campbell. The cave you dare not enter contains the treasure you seek. And I thought I would be just a guy who's Trying to make money in the hedge fund space. And now I realize that I have to engage with the disease that I have, which actually comes from the Thomas Mann, um, the magic mountain as well. He says somewhere in the book that you have to engage with your own disease, if you like. And so I'm engaging with my disease, if you like, because, uh, it seems like that's what I have to do in my life. That's what I'm being required to do. And so that, uh, the start is to talk to you fine folk and maybe I hope to come to the conference in Minster and learn more. Um, I will ask this question, though. In a certain sense, all we care about the patients is just cure me and let me live my life. You don't want to have a disease, and is it really helpful? I mean, in a way, what we want is just to be cured without having to think too much about it. I'm not being given that option, so I will be thinking about it. But, um, is it really helpful? I mean, in surgery, you don't want a guy like me looking at you while you do the surgery, because it's a, you know, you just want it to be 100, focused on what you need to do. So, um, it's a bit of a woolly question, but I don't know if you want to try and answer it.

Speaker C: You could answer it with it very much depends. It's very, very, uh, different for every individual. I, uh, think, um, it can be a good strategy. Uh, so we're just. For. For the doctor's perspective, it really doesn't matter. So we're. We're doing our job no matter what. If the patient engages with his own disease, uh, that we're. We're happy to help and happy to talk, uh, about the disease and give all the relevant information. And we also have patients who are doing the exact opposite and just saying, do whatever is necessary. Um, just. Just treat me. I don't want to. I don't want to look at the mri. I just want you to do your thing. Basically. I, uh, think it's. It's different for every patient, and you have to find your own strategy for yourself to get, get along with this disease that you have and that you're being treated for, and there's no right or wrong way. And certainly, uh, for some individuals to get as much information as you can about your own disease, uh, is helpful. And for others, it can be not harmful, too. So it's very, very different.

Speaker A: What I want to know is, um, because you know, you're both scientists at the end of the day is what delivers the better outcomes. I'll do whatever it takes. If like engaging with disease delivers better outcomes, I'll do that. If not engaging with disease delivers better outcomes, I'll do that. I'll do whatever it takes to ensure the best outcome. If you like, you know, but I guess there's no scientific data on that yet.

Speaker B: I'm not aware of such data. But there's a, there's an old field, you know, facing that that's called psycho oncology. It's how you deal with a disease. Um, and you um, we have a service where we uh, where we treat patients, um, by specialists on psycho oncology and that, that we ah, know that mood plays a role, we know that sports plays a role and uh, so many different uh, other things we call supportive medicine around cancer. Um, and that is important. But I think it's a philosophical question you're raising. I think everyone, everyone has to find his own way. And, but at the end of the day I think best case scenario is that you are going to, that you're guided by your doctor. Right? And maybe also throughout the path your, your, your views will be changing and you will enter the cave or you will leave the cave or escape, whatever. I mean um, that's a, that's a really physical philosophical question here.

Speaker A: I know that every time I do sport, I just like, I specifically for this podcast and want to make it a consultation with a doctor. But um. So um, I find it interesting that during this period however I feel whether I have a one headache or a two headache, whatever the level is, when I do sport it doesn't get worse and when I just do sport, it always feels better to me. Always, always at the end of the day. So I find movement is very important. I'm going to give professor, uh, Pepper and then uh, you, uh, professor mutter the last final word before I say thank you and goodbye. It's been a wonderful time. I really appreciate you spending the time with me and whatever audience we managed together to get together. Dr. Pepper, final words or anything that you missed.

Speaker C: Yes. So um, I wanted to return the thank you for you, for first of all, for you, uh, participating in our trial, um, first and foremost. So uh, this is something that we as researchers are always, uh, always, always very grateful for because um, if you, if you go to conferences, um, you and you see people presenting their work, uh, something that's written on all the, on all the slides at the end, uh, when it comes to, uh, thanking people and thanking collaborators. Um, it mostly always says we also, we. We thank our patients and their families for participating in the trial. And when you first start in this, um, in this cosmos of. Of medicine, you maybe think it's a little bit of. A little bit weird or that it's something that's expected. But if you really engage in clinical trials, you really understand that it's something that you are for as a. As a doctor, as a treating physician. You are grateful for the patients who are. Put their faith in you and, um, that you try to do your job and um, giving them your time and your. Your health for. For that matter, uh, just to, um, to get well themselves but also help you to, uh, try to change something and develop something that's been beneficial. So very, very, uh, much, uh, thank you on that regarding that, and also very much thank you for the, uh, possibility to speak about the trial and the treatment and the perspectives here in Germany.

Speaker A: I'll. Yeah. So thank. Thank you. I'll have something to say about that, but I'll. I'll get, uh. I'll get Dr. Mutter to go next, and then I'll finish up with something that you will enjoy.

Speaker B: All right. I would like to take the chance of closing the loop by saying, um, um, um. Please invest into, you know, medical companies. And this, this is what keeps the system rolling. It's very important for us to work with, especially in the. In the surgical field, to work with medicinal product companies, try to invent new, uh, new devices that we use to improve, uh, surgery, improve outcomes at the end. Um, and not everything can be done by public funding. And um. And it is of course in the interest of. Of. Of. Of all those companies to bring their product onto the market and they need in investors. And um, this is how, how this all works. And, um. And I just want to take the chance of. I know it's a risky business. Um. Um. I. I couldn't. I couldn't tell because. Because I, I.

Speaker A: But, um.

Speaker B: I know that, that. And we were working together with companies that really rely on this and trials that couldn't be done without that. And that's the reason why I just want to say, uh, these words, and

Speaker A: I just want to add that if, um. If any. So I'm not a. I might become an investor in a small way in companies, um, that may save my life. Who knows? But, uh, if you like, you can probably find that you weighted them directly, but I would strongly encourage, uh, the two of you to be involved in the investing side as well, even if founder, uh, companies, uh, or take some technology that you have that you can get patented and uh, so we can talk about that sometime in the future. You, uh, should know that, um, I pride myself where I. One of the questions that I asked Dr. Pepper at the end of the day, I just wanted to know that I was a good patient and that I was, um, liked by the staff and uh, I'm a certain personality. So I was not to say difficult, but there was a huddle, there was a Wednesday morning huddle of the group that go rounds together, uh, and I was totally out of line rushing to the hospital to one of the doctors. There's one person that, uh, doctor, uh, Mutra, I don't know if you know about, but so I was so scared because he's a male nurse, an older male nurse. And, uh, I thought, no, he's not going to be. He's not going to be good for doing a blood sample for me. I'd rather have a young, kind of cute looking nurse. And it turned out that he was the best nurse ever. He finds the most difficult veins. And he even has a name. Uh, it's okay if I mention his first name? That's okay, isn't it? Uh, so his name is Mustafa and he's known around the hospital anyway, so, uh, it's a privilege for me to have met you. I would just say as well that I really am blown away by, um, how dedicated the two of you are and other people are to healing patients and advancing signs. And I think that, um, in a different world, we would have less hedge fund managers and finance people and more people like you would make a better world. And maybe this will contribute to that. So thank you so much. I look forward to seeing you, uh, as a patient at some point. But I, uh, hope that that all goes well and you never have to treat me ever again. So, um, who knows? We'll see. Thank you so much.

Speaker C: Thank you, thank.

Speaker B: You.