Andrew E. Sloan, MD, MBA, FACS, vice chairman of the department of neurosurgery at University Hospitals-Cleveland Seidman Cancer Center talks about a new method of combination treatment that is giving GBM patients a chance at living longer.
Excellent. Let’s talk a little bit about glioblastomas. There are a very difficult cancer to beat. Why is that?
SLOAN: Well, they’re one of the most malignant cancers known to man. And one of the two biggest challenges are that firstly, they’re in the brain. So, this is the organ that really makes us who we are. So, they’re very, very difficult cancers. They can change your personality. They can affect your abilities and your function. And also, one of the things that’s interesting biologically is they are very immunosuppressive. They turn off the immune system more than almost any other cancer known to man.
So how do you see these patients that are impacted by glioblastomas?
SLOAN: Well, I see them when they’re referred to me in consultation when they come often with seizures or weakness or numbness or headache or any one of those things. But these are patients who are very vulnerable. And, you know, this disease can really steal the very essence of who they are. And so, this is a very difficult cancer for many, many people.
So traditionally then, how might you treat it?
SLOAN: Well, traditionally, these patients are treated first with a biopsy and-or a resection, in other words, an operation to take a piece or usually remove as much as safely possible. And then they get radiation and chemotherapy. That’s the traditional treatment.
So, is reoccurrence likely will be a malignant glioblastoma?
SLOAN: Unfortunately, almost all these tumors recur, even with our best surgery and our standard of care treatment, we do not have any known cures. That said, people are doing better and better every year because of some experimental treatments that we’re instituting and some novel ways we use to improve surgical resection and radiation and chemotherapy as well.
But now with laser interstitial thermal therapy, it’s (unintelligible) or LITT in combination with the drug Pembrolizumab.
SLOAN: Pembrolizumab. So let me explain to you what LITT is. LITT was, you know, as a neurosurgeon, I’ve been practicing my field for several decades. And because it’s important to get out as much tumor as safely possible, we typically make a pretty, you know, a reasonable sized incision in the skull because we want to see the tumor as we take it out. And we have very fancy microscopes that we use in the OR and computers that help us navigate in the brain. And that’s been sort of the standard of care for more than two decades. But at the same time, I’ve seen my colleagues in general surgery use these minimally invasive approaches, endoscopy in particular. So, they have a small tool that basically shines a light on the tumor and has a video. And the surgeon, instead of looking directly into the patient is looking at this video camera and the other portal is a tool. And so, he’s got two small incisions instead of one really big incision. So, for example, when they operate in the belly, they used to make one really large incision. Now they make two tiny ones, and they can do a lot of things through those tiny incisions. Endoscopy doesn’t usually work really well in the brain for a variety of reasons. You can’t move the organs in the brain aside without damaging them. But I’ve been working for years to try to figure out how to do a less invasive operation that was still effective. And when I was recruited here, one of the things that brought me here was the three tesla MRI at Seidman that’s in my operating room. So, I actually have an MRI in my operating room. And I thought, wow, the resolution of this three-tesla magnet, standard magnet is one or 1.5 tesla. A resolution at three tesla is so good that I wonder, is it possible to use the MRI instead of my eyes? Maybe I can operate and use the MRI as my eyes instead of making a bigger incision and using these fancy microscopes. But the question is what was a tool? And about a little over 10 years ago that one of the chairs of biomedical engineering at Case actually designed a way to tell temperature with MRI. And my first thought is, you know, who cares? Why would you want to know the temperature with the MRI? And then I began to think, wait a minute. What if you could cook the tumor and you know what temperature to cook to and you could use the MRI to tell the temperature and that gets you this minimally invasive approach. So about 10 years ago, we started this trial. In fact, 13 years ago, we started this trial where we took a laser just with one trajectory. And instead of making a big operation, just a small incision in the skin and in the bone, put the laser on the tumor and cooked it using the MRI to guide the temperatures. And what we found was we could actually damage the tumor and significantly extend survival using this minimally invasive approach. And so that has become very exciting. And we’ve refined it through several generations of technology. It’s better and better. Unfortunately, it’s still not a cure. It’s not really situated for all kinds of brain tumors. It only works in certain kinds of tumors and in certain sorts of anatomical configurations. But in those patients, it can be very effective. Still not a cure, though. And so, the next thing I thought, what if we could combine this heat with an immune therapy that would allow the brain to attack the tumor that’s been partially damaged by the laser? And that is how this trial came into being. Many cancers can actually suppress the brain. The way I explain it to many of my patients is, you know, most people have read the Harry Potter books. Harry Potter is this magical figure who has a number of tools. But one of the things he has is this tool that he calls a cloak of invisibility. He puts it on, and he becomes invisible. Well, tumors have sort of the ability to create this cloak of invisibility, if you will, by hiding themselves from the immune system. And so, my thought was, if you can burn the tumor and damage it enough and then use this drug called Pembrolizumab, which is what we call a checkpoint inhibitor, you can not only damage the tumor, but also erode that cloak of invisibility. And that’s sort of the theory in a layperson’s terms behind this trial. And so far, we’ve been very pleased.
Is this being done anywhere else?
SLOAN: Well, not for GBM. We’re the only place that’s doing it in GBM, but a couple of other centers have asked to join us. And we’re in the process of negotiating that. And so that might happen in the next few months.
Are there any other risks to consider, like damaging any of the surrounding brain tissue?
SLOAN: There are always risks for brain surgery. And it is possible to damage the surrounding brain tumor. And that’s why when we do the LITT, L-I-T-T stands for laser interstitial thermal therapy, we’re actually monitoring the temperature in near real time. So, when most of the temperature increases in the tumor itself, which is the desired effect. When the temperature starts to rise in the areas of the brain that are outside the tumor but nearby, then we stop. And the reason that we can do that now with this modern technology is that we can actually monitor the temperature almost voxel by voxel. So, it’s very precise. And when the temperature gets too high, we just stop treating or let the tumor cool off and move the laser. And we have some lasers that are directional and some lasers that go in all directions. And so, we can sort of sculpt the treatment as we need to do to maximize the treatment of the tumor and minimize the damage to the surrounding brain.
So, you’re spearheading this trial, correct?
SLOAN: Well, it’s the only place it’s open right now is here at UH in the Seidman Cancer Center.
And you have oversight of all that, right?
SLOAN: Correct.
So what are some of the specifics about what you’re doing with the trial? What kind of things are you looking at?
SLOAN: So, we’re looking at patients with recurrent GBM. These are patients who had a glioblastoma, got standard treatment or in some cases experimental treatment, which is typically standard treatment plus something else, and then had the tumor come back. But they’re generally people who are doing pretty well. And what we do is we do a biopsy of the tumor. We set up the LITT and through the same trajectory, we start with a biopsy. And if we see tumor, then we put the laser in and we do the laser. The experimental part, you know, LITT is now an FDA-approved procedure. It wasn’t when we started doing it 13 years ago, but we really helped put LITT on the map. It’s becoming more and more common. Pembrolizumab is an approved drug for many kinds of tumors. But Pembrolizumab is not FDA approved for GBM and the combination is not FDA approved. And that’s why this is a clinical trial. So the challenge here is that we, based on some anecdotal data in other tumor types, we have always felt that the best and most effective way to do this was to give Pembrolizumab up front perhaps a week before the surgery and then do the LITT. But that also has the highest risk of side effects. And so we started out just to be safe by giving the LITT and then giving Pembrolizumab afterwards. And then we moved Pembrolizumab up still afterwards but very close afterwards and we didn’t see any side effects. And so now we’ve done our third patient with Pembrolizumab, the checkpoint inhibitor up front and followed by the laser. And we think so far this is the most effective way to do it, which is what we always suspected. But fortunately, we’re not seeing some of the side effects that we thought we might see, which is why we chose this sequence last. And Fran Noonan is one of those patients. She’s the first patient on this arm, first patient who got the checkpoint inhibitor prior to the laser. So, Fran Noonan was the first patient in that third arm who got Pembrolizumab up front, followed by the LITT. And so far, we think it’s very effective. The tumor basically seems to have disappeared. Now, you know, so we’re very, very excited about this.
Let’s talk a little bit about Fran. We’ll kind of go out of order here a little bit. So, she was a good candidate, obviously?
SLOAN: An excellent candidate. Well, she was, well, she was in good shape. She’d gotten standard treatment and it unfortunately had failed. But as I said, that’s unfortunately, this is not typically a curable tumor using standard treatments. And she came to see us and was willing to do this experimental treatment. And she’s been terrific. She’s made all her follow up visits and we’re really excited for her. She’s doing extremely well.
So, let’s go back to this a little bit. With LITT, with the use of LITT, how often would patients need to receive a treatment?
SLOAN: So, the way this works is they get the Pembrolizumab, the immunotherapy a week before surgery, and then every three weeks for up to six months. The surgery is only a one time thing. So, they get one surgery. If they needed it, they could get a second surgery. But that would be off the trial. You can do more than one LITT but the trial is a single LITT surgery.
We’re not really calling this a cure, are we?
SLOAN: You know what? I hope someday we could call it a cure, but we’re not ready to say that.
What about remission? And glioblastomas are tough, aren’t they?
SLOAN: They are a very tough tumor. Put it this way, Miss Noonan is doing great. And I would say she has no signs of tumor right now. I think remission is a word that we probably won’t start using for a while. Technically, you know, you want to be free for five years. So, we’re not quite there yet.
So how many months or years are you hoping to give back to these patients?
SLOAN: Well, I’d love to cure them. You know, I’m not telling you that we are curing them because we don’t know yet. But that’s obviously the goal of all this is to cure GBM.
So, are you personally seeing a response to LITT other than Fran?
SLOAN: Well, you know, it’s an early-stage trial. But yes, we do seem to be seeing responses. The question is, is this statistically significant? We can’t really say until we finish the trial. That’s part of the ethics of trials.
So, your future hope, as you said, was to make this a cure and hopefully this would be a cure.
SLOAN: Correct. Well, I mean, you know, we obviously hope to cure GBM. I’m not ready to say we have a cure yet. I want to make that clear. I’m not saying this is a cure, but that’s obviously the goal. And I think between LITT and immunotherapy and some of the gene therapy work we’re doing, you know, I think there’s certainly promise. I don’t think we’re there yet, but we’re clearly doing a lot better than we were a decade or two ago. So, I mean, we’ve made a lot of progress and it’s very rewarding.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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