Michael Vogelbaum, M.D, Ph.D, the Associate Director of the Brain Tumor and Neuro-Oncology Center and a neurosurgeon at the Cleveland Clinic, talks about a study of a new therapy for deadly brain tumors.
Interview conducted by Ivanhoe Broadcast News in July 2016.
Can we talk a little bit of background, of the trend of using viruses to treat brain tumor, it seems like it’s been popping up in the news here and there.
Dr. Vogelbaum: There’s been decades of interest in using viruses to treat brain tumors Uh- most of the focus early on has been on using viruses to deliver therapeutic genes in to brain tumor cells. This is not only for brain tumors but for other cancers as well. There was a lot of work early on that showed that viruses could deliver genes to brain tumor cells in patients, he problem being delivering the genes to enough cells. There’s been a progression of work over the past decade, decade and a half that’s helped us to learn how better to deliver therapeutic genes to brain cancer cells. This is a new approach that builds upon all of the work that’s been done in the past and now we’re starting to see some early signs of success.
Let’s talk about your study that’s coming out. What were you looking at and what were the results?
Dr. Vogelbaum: This is a study that was looking at a new type of virus to deliver therapeutic genes to brain tumors. This is a virus that had not been used in humans before, this was the first experience. It had a number of advantages most viruses that have been used in the past for human studies are viruses that we encounter on a regular basis. For example, the common cold virus has been used for delivery of genes to brain tumors. We have developed great mechanisms to fight off infections by viruses like cold viruses and other viruses we normally see. This is a virus that humans don’t normally see and so there is not a built in immunity to the virus and it’s been very effective in delivering the therapeutic gene. That’s been one advance here. The other is the gene itself, this is a gene again that is not normally expressed in human cells. It’s a gene that comes from yeast cells. The medication that is given is relatively nontoxic to normal human cells and it’s only cells that have this gene that can convert it into a toxic chemotherapy. That’s been another real advance in this approach is to use that combination of a virus that has not been used before and in a gene that is not present normally in humans.
Can you walk us through how the virus is delivered, the process of the treatment?
Dr. Vogelbaum: For these studies the virus is delivered directly in to the brain, in to either the brain tumor itself, the solid tumor, or in to brain that has tumor cells that are invading in to it. Both approaches were used. In one approach the virus just delivered in to the solid tumor and then is allowed to spread within the tumor before the medication is given that ultimately exerts the clinical benefit. In the other approach we take out the worst part of the tumor, the solid tumor and then once we’re done removing the solid tumor we inject the virus in to the brain immediately around that solid tumor. We know that there are invading tumor cells there that we cannot remove safely. In this case it’s treating what we call the infiltrative tumor.
Is it put in with a catheter system?
Dr. Vogelbaum: This is directly injected with either the biopsy instrument that we use if we’re not removing the tumor or with a special type of needle that is safe for placing in to the brain and where we can do the injections.
What have the results shown so far?
Dr. Vogelbaum: The initial focus of the studies was on several different important aspects of a new type of therapeutic. One is: is it safe to give the therapeutic and at what dose is it safe. There were a series of groups that were evaluated at different concentrations of the virus and different concentrations of the medication that’s given afterwards. We reached a level of virus that we felt was going to be enough virus to give, we really never saw much in the way of toxicity with the virus and we found a level of the drug that was also safe to give. At the same time there were some studies being done looking at whether or not the virus actually was able to deliver the gene in to the tumor successfully. We saw that the gene was delivered and since genes code for proteins and it’s the protein that ultimately that’s responsible for converting the relatively nontoxic drug in to the chemotherapy we saw that the protein product was present in the tumor cells. It showed that not only could we give a safe dose of the virus but it was enough to actually get the affect that was intended.
And how did the patients do that were on the drug?
Dr. Vogelbaum: It’s a little bit hard to really access clinical benefit in a series of Phase I trials which these were. Certainly we saw patients who did well and we believe that they did well because of the treatment that was done. Ultimately that’s going to require proof in a randomized trial and that randomized trial is now open. We’ve already enrolled patients and treated patients on that trial. That will be the definitive evidence as to whether or not this is an effective therapy for patients with brain cancer.
The main outcome of this study then was that it was well tolerated by the patients and that the protein was there that you need for the drug agent to actually work.
Dr. Vogelbaum: Correct.
What is the ultimate goal in the end, what is the virus and the treatment designed to do in the next phase of trials?
Dr. Vogelbaum: The next phase trials are focused on the most important thing to us. Does this really work for patients, does this slow down or even stop their brain tumor. That’s what these studies are focused on. Along the way we’ll be evaluating some other aspects that may be important for them to work. Things like how they may stimulate the immune system or whether or not stimulation of the immune system helps to even increase the benefit. We don’t know all of those answers yet. This next study is really the first attempt to look at how effective it is in a wider range of patients with brain cancer.
What would you say is the main take away message at this point for people at home who are curious about this or may have a loved one or someone they know fighting brain cancer.
Dr. Vogelbaum: I think the most important message is that we have an entirely new type of treatment that has shown promise in early studies and is now in what’s called a pivotal trial. One that could determine whether or not the FDA will approve it as a more generally wide spread therapy. There are very few new treatments in the world of brain tumors that make it to this point where they actually are subject to randomized trials and ones that the FDA will be watching very carefully for possible approval. This is one that has overcome a number of the thresholds necessary to show that it has real potential. Now we’ll see.
Were you surprised by the results?
Dr. Vogelbaum: No I wasn’t surprised by the results; I think that the entire idea behind this approach is a sound idea. As I said it’s building upon an experience that has been generated over the past decade and a half. A lot of the early lessons that we learned were incorporated in to the design of this therapeutic so it really started with a lot of promise.
I would like to get a very simple, concise response as far as what the virus is designed to do.
Dr. Vogelbaum: The virus is really a package for delivering a therapeutic gene to a cell. There are different approaches used with viruses. In this case it’s for gene delivery. There are other virus approaches where the virus itself kills the tumor cells, that’s called an oncolytic virus that’s what this is. It infects the cell and turns it into a factory to create more virus that then spreads within the tumor. The therapeutic gene is also incorporated in to the tumor cells along the way and that’s what allows the relatively nontoxic drug to be converted in to a chemotherapy only in the cells that have that therapeutic gene. Which in this case is for the most part the tumor cells.
Can we talk a little bit about Francois?
Dr. Vogelbaum: Sure.
What was his prognosis when he first came in, when he first started to receive the virus?
Dr. Vogelbaum: All patients that were treated so far had a high grade brain tumor that was already refractory to prior treatment. That means that they had undergone surgery, they had undergone radiation therapy, they had undergone chemotherapy and their tumor was growing again. Once people reach the stage of recurrent high grade glioma the prognoses is not very good. It can be somewhat varied from patient to patient but in general these are patients that are looking at a survival of months not so much years. They start off in a difficult position and he’s done very well with this treatment.
How long has he been receiving it?
Dr. Vogelbaum: He underwent surgery and the viral treatment in 2013, so it’s been almost three years, about two and a half years now.
Can you describe how his tumor responded to the therapy?
Dr. Vogelbaum: I’m going to have to review some of the records to be sure. I wasn’t sure we were going to be talking about this so much.
That’s okay.
Dr. Vogelbaum: I can’t remember if he was on injection or on the resection protocol.
Maybe in general of the patients who are doing well, how have the tumors in general responded?
Dr. Vogelbaum: When you use the terms response it actually has a specific meaning in our field. We measure the tumors by looking at, for the high grade tumors; we measure them by looking at the contrast uptake. When the portion of the tumor that takes up contrast shrinks we call that a response. When we do surgery to remove the enhancing tumor then it’s very hard to evaluate response. Now we’re more focused on how long it takes before the tumor grows again. That’s called progression. We’ve had some encouraging results in terms of delaying progression and encouraging results in terms of what really matters in the end which is overall survival.
How is Francois, is he able to do everything he wants to do and basically how is he living his life?
Dr. Vogelbaum: Francois is probably the best source for that information but from our standpoint he is alive, he is working, he’s living his life and that’s all we can ask for.
Anything that we missed that you think is important to mention?
Dr. Vogelbaum: The one question I was surprised you didn’t ask which is, how does this compare to what was presented on sixty minutes.
Was sixty minutes the polio vaccine?
Dr. Vogelbaum: It’s the polio virus.
That’s what I meant.
Dr. Vogelbaum: It’s the polio virus. That’s why I threw in the oncolytic virus because that one is an oncolytic virus.
So how is it different?
Dr. Vogelbaum: This one is different in that it is delivering a gene that then makes the tumor cells more sensitive to a separate medication that’s administered. What makes therapeutic gene delivery different from an oncolytic virus is we have a lot more control over the intensity of the treatment. One of the challenges with oncolytic virus is they can spark a very robust and sometimes overwhelming immunological response. Whereas in this case while the immune system probably is involved in the response it’s a milder response and one that’s more controllable with the dosage of the medication that’s administered afterwards.
Anything else we should touch on?
Dr. Vogelbaum: No I think that pretty much covers it. Do you want to talk about our role in the study?
Absolutely, I was going to ask if we should refer to this as a Cleveland Clinic study or a joint study?
Dr. Vogelbaum: This is actually a company sponsored trial. The Cleveland Clinic was one of the first three sites that started this clinical trial. We have been one of the leading sites in terms of putting patients on the trial. In terms of treating patients let’s put it that way. One of the leading sites in terms of treating patients with this therapeutic. We also did some of the fundamental work in trying to understand how effectively we were able to deliver the virus to the tumor cells themselves. We’ve been involved since the very first patient was treated in a clinical trial.
Are you the PI on this study?
Dr. Vogelbaum: It doesn’t quite work that way when it’s company sponsored so I’m one of the three who got the trial going. There was myself, Dr. Tim Cloughesy at UCLA and then Dr. Manisha Israni at UCSF, we were the first three sites. We’ve been involved in both treating patients and also providing advice to the company in terms of how to proceed, and whatever questions are important to answer along the way.
END OF INTERVIEW
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