As Chair of UCLA’s Department of Neurosurgery and the inventor of a personalized brain cancer vaccine, Dr. Linda Liau is widely recognized as one of the world’s most forward-thinking brain surgeons. Having spent more than 25 years on glioblastoma research, Dr. Liau developed the individualized treatment to work with a patient’s unique immune system to detect and attack cancer cells that remain after tumor removal.
Glioblastoma, the most aggressive type of cancerous brain tumor, usually results in death within 15 months of diagnosis. One of the biggest problems with finding a successful treatment? According to Dr. Liau, the fact that the disease is so heterogeneous – that it presents differently from patient to patient – means that the standard clinical trial approach has so far been less than helpful when it comes to identifying a cure.
So, what is the answer? Ever the pioneer, Dr. Liau thinks that comparative analysis may be a good start. Such an approach would allow physicians to treat patients individually, using real-word data to treat the patient according to what is best for them, rather than by strictly adhering to the protocols of a standard clinical trial.
I recently sat down with Dr. Linda Liau to discuss glioblastoma, the current state of clinical trials, and how a different approach is needed to eventually find a cure.
Q: What, in your opinion, is the big-picture problem with glioblastoma?
A: I’ve been working in this area for 25 years now, and one after another, these trials fail. AbbVie had a trial just a few months ago that failed and I think biotech caption was, “Glioblastoma takes another victim.” So, I think we’re going about this the wrong way, because I think everybody’s trying to find a cure but also have a company raise money and get their company launched. But glioblastoma is such a heterogenous disease. I don’t think you could go say, “Oh, I have one drug or one treatment, one molecule target or one drug, and I am going to patent this, license it and then do a startup company. And this is how I’m going to cure GBM.”
More and more, I do think you need to think about appropriation therapies, we need to think about timing of treatments and also the whole process of getting therapies adopted through the whole hurdle of FDA approval.
For instance, consider the trial that I’ve done for dendritic cell vaccines. For cellular therapies, I think what is lacking is a smooth, operational aspect. Let’s say, if there was a company that could make GMP-grade cells readily and basically, it’s almost like the manufacturing, production, distribution, and coordination of the treatment or clinical trial for approval for a treatment would go much more smoothly.
I think that’s what’s lacking. And the ideal company would be like, almost like an Uber or Amazon. Basically something that turns and existing industry upside down. I think we need something that turns the—not only the clinical trial to FDA approval process upside down, but also how to scale that up once something is approved or adopted.
That’s also a struggle, because a lot of things we develop in academia that are interesting, like the cellular therapies, are very hard to scale up. And you could develop less interesting things like single-target molecules, but so far those haven’t really been useful for GBM.
Q: How can we use software take everything that’s out there and make the trial process more efficient?
A: Right now, we’re starting up a trial, which personally I think would be very promising. It’s basically using vaccination in combination with a PD-1 inhibitor. We’re working with Merck on that in combination with Poly ICLC, which is a Toll-like receptor. That’s another company called Oncovir.
So, with a DC vaccine, like I said, we can just make it ourselves. We can’t scale up as an academic institution or a small company, but if that were part of the company we could scale up. To make the vaccine, you just need a manufacturing GMP facility. But the problem there is the autologous dendritic cells are hard to get patented. You could patent it, but it’s hard to defend that because it’s really the patient’s own tumor, right?
So, the patents really are process patents and we could file one that tweaks things a little bit, and that’s essentially that’s what Northwest Bio did. They filed multiple patents just on little tweaks of the cocktails that are used to make the cells.
The other drugs are already made by other companies and they’re just an agreement. How do you patent something that is actually part of a patient rather than just patenting the process? And that’s why people have gone on to patent just individual targets. We could do that, but I wouldn’t invest millions of dollars on a clinical trial to do a trial of a vaccine for an individual target. I just don’t think it can work. So, I think the conflict is you could patent some—you could say, “Oh, I discovered this one protein that we can make a vaccine to and we could license it.” But my gut feeling is that is not going to be what will cure GBM. In a way, what I think will cure GBM is unpatentable. So that’s the dilemma. Does that make sense?
Q: Do you feel that that in order to find the cure, we have to flip everything upside down and approach it differently?
A: Yeah, and so the problem is because of the financials, we get approached by VC’s that want to start a company. Obviously, there’s a way of doing this, right? You think of a way of doing it. Big Pharma does the same thing. It’s like, “What’s your drug? What could we do with it?”
It’s been successful in other areas. A lot of my colleagues here have done very well with prostate cancer drugs and breast cancer drugs. But so far glioblastoma and pancreatic cancer are both very formidable, and we haven’t gotten there with these small biotechs or Big Pharma companies coming to us and saying, “What do you have?”
And we give it. We either license it out or start your own little startup. Here at Stanford, it’s a very start-up environment. It depends on your goals. If your goal is to have a startup and then have a pharmaceutical company buy you out or get an IPO, you could do that. We could do the same thing Northwest Bio, Tocagen, Selbach, or any of these companies that have already done trials do.
But at the end of the day, it doesn’t really cure GBM unless there’s something a little bit broader. I guess in my heart of hearts, I think what’s going to cure the disease is going to be personalized. It’s going to be something that comes from the person or the tumor itself and I’m not sure how that can be patented other than the idea and the process by which that’s done.
Q: Why is it so difficult to find the cause of glioblastoma? Why can’t we find the cure?
A: Yeah, I think it’s just too heterogeneous of a tumor. The cause is not one thing and it’s not the same thing for each patient. And also, not for each patient at any point in time, because the tumor also changes over time. So, you’re really looking at four-dimensional variables that are changing.
To say, “oh, I have this one treatment that’s going to be able to deal with all that,” is unrealistic. And that’s why I think ultimately at least in terms of dealing with the heterogeneity from patient to patient, you have to come up with more patient-derived or patient-informed treatment. Not something that you just take off the shelf and give to everybody.
Because I think with all these little trials that we’ve done over the years, there are some people that responded, but the majority of the patients don’t. Then the trial fails, and we really don’t learn anything about it. It just needs to be a process involving finding mathematicians or bioinformaticists who are skilled in terms of how you deal with a problem where you have moving parts in four dimensions.
Q: How much is the blood-brain barrier a part of that four-dimensional moving part? Is that one of the four dimensions in your mind as you described it or is it just another impendent into the problem?
A: Yeah, I think it’s another impendent into the problem. Delivery is certainly an issue because of the location. It’s an issue for other things as well. Even in immunotherapy, the immune response is different in the brain. I remember when I first started, people used to say that you can’t get an immune response in the brain.
I think now people think otherwise. You can, but I think it’s different than the rest of the body. It’s just not the same type of response. So that plays into it, as well as getting drugs into the blood-brain barrier. I would say all of the above.
Q: Is there anything else in that big picture that people should know or be thinking about specifically around glioblastoma?
A: Yeah, I think people have to think about the patient when we design these trials. A lot of times, we design these trials and end-points based on the way we design the mast studies. We have a treatment group and we have a placebo group. Then, at the end we’ll see which group does better.
And I don’t think in patients you can do that. And honestly, if I were a patient, I’d hop from one trial to another depending on what sounds promising or what’s available at that time. A lot of patients do that, and then you really cannot necessarily control for that. Let’s say someone took TOPA and then went on another trial. Was there any effect from the virus that they had before?
So, I think that’s an issue in terms of when we design these trials, what should we have in mind? We have the patient more in mind. And I think, broadly speaking within the field of neurosurgery and neuroscience and not just brain cancer, a lot of people are advocating for what they call comparative analysis. Not necessary using randomized clinical trials as the gold standard but using real-world data.
For instance, how would you actually treat this patient? Not how would you treat this patient based on the protocol in the clinical trial. Because a lot of times, as a physician, what we want to do is what’s best for this patient. And sometimes, it’s not necessarily congruent with the strict protocol procedures that you have to abide by to keep a patient on the clinical trial.
And then it’s hard because patients have access to information on the Internet and shop around to get different things. For instance, I must get a dozen or more emails or calls every week from random people about how they can get the dendritic cell vaccine, DCVax. And personally, I can’t—one, I can’t do that on a clinical trial. But even if it was FDA-approved, unless it’s covered by insurance how do you pay for them?
So, how do we fix that problem? All of these trials fail because the treatments don’t work, but I think a larger part is we’re not designing the trials right. But part of it is that it’s difficult to provide these trials if you truly want to do what’s best for your patient.
Q: Can you explain more about the difficulties in designing the trials to do what’s best for the patient?
A: For instance, I’ll just take what happened with the DCVax. You really want to get clean data. We’ve never allowed for patients to get the vaccine once they failed, because they will. You enrolled in the trial. You had a recurrence, and now you’ll have to try something else.
I could tell you patients are fighting to get the vaccine. And even if you tell them, “Well, there’s no proof that this works. This is the whole reason we have to do the trial. I can’t tell you that there’s any benefit.” But I guess the counterargument that I hear quite often is, “well, the side-effects aren’t bad.” And they’re not. So, it’s like, “Well, if it’s not going to hurt me why can’t I have it? Why can’t I try it?”
Because of that it’s hard to prove something based on what the FDA requirements are without being a little cold-hearted and saying, “Well, no, you’re not allowed to try that.”
So, a part of it is having the FDA think a little bit differently about what constitutes approval. On the converse, like the Optune device, that Novocure device, is FDA-approved. But I must say a lot of patients are like, “Well, I don’t really like it.” And I think on the physician side, we just don’t understand how it works and there are a lot of problems with the clinical trial design.
There was no true placebo arm, but they did design it in a way that met the FDA checkboxes. So, it was approved, but a lot of us don’t really believe that it works. I think it’s one of these things where if your ultimate goal is to cure GBM, it’s hard to reconcile all these different factors; the regulatory factors, the financial factors, as well as the science and the biology of the tumor itself, which is very complex.
Q: Got it. Sounds like we have our work cut out for us.
A: Yeah, but if your smart people can figure this out, I think it could be done. It’s been done in other fields, but I think it just takes a different way of thinking about it, and it’s not the “Eureka!” moment of, “oh, I discovered something in the lab. I’m going to take it to clinical trial, launch my startup company, and charge ABM.”