Immunotherapy for Glioblastoma with Adam Sonabend, MD

Amanda Dee: Immunotherapy is becoming an increasingly effective treatment for many types of cancer, though not for glioblastoma, one of the deadliest cancers. Neurosurgeon and Feinberg associate professor Dr. Adam Sonabend joins us today, however, to discuss a promising study on the potential benefits of immunotherapy for certain glioblastoma patients. Thank you for being here.

Adam Sonabend, MD: My pleasure.

Amanda Dee: To get us started, tell us more about what led you to pursue neurosurgery in the first place.

Adam Sonabend, MD: I've always been interested in doing things with my hands and I was very much enjoying anatomy early in medical school. And I was also really drawn to cancer early on for biological interests and for the fact that I thought this was a fascinating disease. So neurosurgery was a way to merge all these interests into a single career, studying cancer, doing surgery, and being related to neuroanatomy. This is what made it happen for me.

Amanda Dee: In clinic, when one of your patients is diagnosed with glioblastoma, what does disease progression look like?

Adam Sonabend, MD: So it depends. Occasionally, Disease progression occurs in the context of an MRI that is done for surveillance when the patient currently has maybe no symptoms. And unfortunately this scan might show that there's been interval growth of a tumor since the last time we had scanned the patient. This is an unfortunate circumstance because the patient might not otherwise feel ill at all, but that leads us to change the course on whatever we had been doing to try to address the growth of the tumor. Occasionally the tumor growth is manifested with new symptoms: headaches, nausea, vomiting, neurological symptoms or signs like seizures, weakness, numbness, difficulty talking, difficulty, understanding language. It's an interesting tumor in the sense that the symptoms are mostly related to the location of the tumor, not so much the pathology.

Amanda Dee: And what does the standard of treatment look like today?

Adam Sonabend, MD: Yeah, so the initial approach to these tumors is well-established. It involves a surgery to maximize the amount of resection you can do while remaining safe. That leads you to often resolve the initial symptoms that were present that led to the diagnosis. And that also allows the pathologist to get tissue, to analyze and to give a name, a last name, and if you will, the molecular nuances to what a particular tumor might be. That is usually followed by radiation. And if the patient has a specific kind of tumor, then chemotherapy with a drug called temozolomide is also thought to be beneficial on top of that. Over the last few years, there's a new treatment has been shown actually to help most people in most scenarios, which is tumor-treating electrical fields. And this is done at the end of radiation. These are basically stickers that are connected to a battery pack that are placed in the patient's scalp, and these electrical currents over time help basically stop tumor growth, at least transiently. So that's really the standard of care for these tumors.

Amanda Dee: Before you started looking into immunotherapy as a treatment for brain cancer, you've analyzed some of these methods that you've discussed in your previous research. Could you give us a brief overview of some of your previous research?

Adam Sonabend, MD: Yeah, sure. So I have an NIH-funded lab where we study basically two things, with the idea that the combination of these two things will hopefully lead to a breakthrough in the treatment of these tumors. One of the two things is figuring out ways to deliver drugs to the brain. As you might know, the brain is protected from the circulation and from whatever is in the bloodstream in the rest of the body by this structure called the blood-brain barrier. And it's a really interesting membrane and complex structure that really keeps the brain from being exposed to most drugs out there. And this is really important for avoiding toxicity and it's actually conserved across multiple species of animals, but when it comes to treating brain cancer, this is really inconvenient, if you will, because most drugs don't get into the brain.

So one of the things we study in the lab is a means to get drugs across the blood-brain barrier. The other thing that relates more to the study that we recently published and we're discussing today is the use of personalized medicine approaches. And so here, the premise is that no two tumors are necessarily equal with regards to how well they will be responding to a given therapy. And in spite of these discrepancies across patients, we tend to just treat everybody the same way and hope for the best, and this leads to no benefit of a given therapy for most patients. So the other thing that we study in the lab is a means of identifying patients that might benefit from a specific therapy. So my hope is that combining a means of delivering drugs to the brain and personalized medicine would allow us to, at some point, be able to repurpose existing drugs and give the right drug to a given patient and at least help a subset of patients with this disease.

Amanda Dee: Prognosis for glioblastoma is on average only a little over a year. And I can't imagine how difficult it must be to have to deliver that diagnosis. How has your experience with these patients motivated or translated to some of your research?

Adam Sonabend, MD: Yeah. So first thing I'll tell you is I'm always very careful when I'm talking to patients not to tell them how long they will live. And that is something I do because I really don't know how long a particular individual will live and it's not really, I don't find it helpful to speculate or to estimate based on averages because most people don't behave that way. So I'm always making the case that it's not about a specific number that nobody knows. But with regards to how this has influenced my research, I will tell you that it is frustrating as a clinician to be dealing with a cancer that whereas I can treat and operate, it's not really a surgical disease in the sense that I can't really have a profound long-lasting control of the tumor by doing surgery. This is not how it works. I can alleviate the symptoms. I can give access to new therapies. I can get a tissue for diagnosis, but I can't have long-lasting control of the tumor by doing surgery. So this has been the motivation to do research.

Amanda Dee: And explain how immunotherapy works in the context of cancer treatment and some cases when it is more likely to be successful.

Adam Sonabend, MD: So it's a really interesting question. You know, immunotherapy has been, hands down, the most important revolution in cancer treatment over the last 10 to 20 years. Several people got the Nobel prize for these. There were cases that, back in the day when I was starting medical school, would be deemed essentially terminal with not much to do. And suddenly, when immunotherapy started becoming readily available, these patients were going into long-term remissions and doing really well. It's really exciting. Immunotherapy is basically a kind of treatment that will turn the patient's immune system and lymphocytes to start attacking tumor cells. And the way it works depends on the kind of therapy, but the most widely adopted kind of therapy that is immunotherapy is immune checkpoint blockade. And so, the way this works is that T-cells, lymphocytes, that might attack tumors have a built-in break.

And this break is very important, 'cause this is really how the body keeps these T-cells from engaging and attacking your own body. And this break is therefore super, super important. Turns out, cancer cells have learned a way to activate this break so that if T-cells, or lymphocytes, can at some point, identify these tumors, the tumors suddenly turn the break on and the T-cells stop doing that. And so, Immune checkpoint blockade, this a means to these allowing that. Basically you turn the tumor cells to be unable to activate the brake so that the T-cells and lymphocytes can attack the tumor.

Amanda Dee: Why has immune checkpoint blockade historically been more difficult to use to target glioblastoma?

Adam Sonabend, MD: Yeah, that's a great question. Well, a few reasons. One of them is because immune checkpoint blockade tends to work best in cancers that are already having T-cells and lymphocytes in the tumor, like cancers that have antigens or, if you will, something unique about them that truly looks very different from the rest of the body so that the lymphocytes can easily identify them. And glioblastoma is neither of these two things, glioblastoma is not a tumor that has a lot of inflammation or T-cells to begin with. And it's a tumor that for the most part, doesn't have that many antigens that look so different, or if it does, they're usually in a subset of tumor cells within the patient. So, you know, getting rid of those cells is not sufficient to control the tumor. The other reason why I think it hasn't been helpful is two other things.

One is because I think it is helpful in some patients, but people can't really tell who these patients are. And so, if you assume that everybody will respond equally, and if you do clinical trial, you assume that all patients will have the same proportional benefit and you designed the trial to prove that, and then usually the trial ends up not proving that and the results are negative. But that does not necessarily mean that there weren't patients in this trial that did really well. The last reason why I think this is a challenge for glioblastoma is because of the blood-brain barrier, as we discussed. So most of these therapies are antibodies, which are known not to really cross the blood-brain barrier routinely. So if the drug is not even where it needs to go, that makes it challenge.

Amanda Dee: And that leads us to your recent study in Nature Cancer, where your team found that a biomarker predicts survival from recurrent glioblastoma, tell us more those findings and why it's important to the larger conversation about glioblastoma research.

Adam Sonabend, MD: Sure. So in this study, we discovered a predictive biomarker, and I will explain what a predictive biomarker is. A predictive biomarker is something you can measure, you can test in a tumor that has not yet been treated that will essentially inform the doctors on whether this tumor will be particularly sensitive or respond to a given therapy, in this case this is the immune checkpoint blockade, PD-1 blockade. And so, we previously have found that tumors that respond to immune checkpoint blockade, glioblastomas that respond to immune checkpoint blockade, have two mutations that are super rare, but are actually way more common in the patients that respond. These mutations are only present in about two to three percent of all patients, but both mutations actually end up activating the same signaling in the tumor. So the motivation to the study that we did is we were perplexed by the fact that two mutations that are super rare were independently pointing at the same signaling cascade. Signaling cascade is how a tumor communicates to itself or tumor cells that they need to grow.

And so what we found is these two mutations were activating the same signaling cascade called MAP kinase. We therefore thought, well, maybe these mutations are really interesting; unfortunately, they're not very useful as a biomarker. They're only present in about one out of three patients that benefit from therapy, but we didn't know how to identify the other two patients. And if you were to offer a patient a study that has two to three percent likelihood of being positive, I don't think most patients will find this too exciting. So what we did is try to determine whether both patients that had the mutation as well as patients that did not have these mutations that end up doing well and surviving long once they get immunotherapy had the same signaling cascade activate. In other words, we hypothesize that the patients that do not have the mutations that live long also have the same MAP kinase signaling cascade activate.

And so for this, what we did is we did a specific staining on the tumors. We can use an antibody that leads to nice coloring of the tumor tissue when this signaling cascade is active. And what we found is that the patients that got immunotherapy that had this biomarker elevated live significantly longer than the patients that did not have the biomarker elevated that also got immunotherapy and also got significantly longer survival than patients that had either high or low levels of the biomarker that didn't get immunotherapy. In other words, in order to live long, you needed to have the biomarker elevated and have undergone immunotherapy. What was exciting about our study is that we then went into a separate cohort of patients from a different clinical trial that was done at UCLA. And we were able to find the same correlation with survival.

Amanda Dee: These are exciting results. What are the next steps for this study?

Adam Sonabend, MD: I think there's two steps that are important. One is in the mechanistic understanding of why this is the case. We found that these tumors tend to have a different environment. So the signaling is in the tumor cells, but the cells surrounding the tumor cells are very different when this signaling is elevated. And so one of the important steps is to understand how tumor cells communicate with the cells around them to make the environment actually permissive for response to immunotherapy. So that's one of the things we're investigating. And from the practical point of view, beyond this scientific understanding, we'd like to apply this to patients. So we we've done a nice study in which we found the same correlation with survival in two separate patient cohorts. And that's really good, but this was all done retrospectively. In other words, the patients had already been treated and we have already gotten the tumor tissue and they have already either passed away or remained alive. And then we did the analysis. I think the next step before this can be adapted into routine medical practice is to do a clinical trial in which we would basically determine the level of the biomarker and treat the patients before we know how long they're going to live, of course. And then determine whether we can confirm what we have already observed. If this can be confirmed in a clinical trial, then this would be very helpful.

Amanda Dee: Glioblastoma is a frustrating and tragic disease, but as we've discussed, the scientific community is approaching it from many angles to find new ways to target it. On a previous episode of the show, we've spoken with your colleague, Dr. Priya Kumthekar about crossing the blood brain barrier with a new therapy. As someone caring for patients with this disease. What other ongoing research and approaches give you hope?

Adam Sonabend, MD: Yeah, there's another research program that I have, a clinical trial going on, which is the use of a ultrasound-based technology to transiently open the blood-brain barrier, and so that's a very promising approach that is not only me, it's several groups are investigating this. Where you basically would use ultrasound waves that are hitting the brain of the patients. And as you do that, there's also very tiny microscopic bubbles that have been injected into the bloodstream when the sound waves hit the bubbles inside the brain, inside the blood vessels, the bubbles vibrate, oscillate and burst, and that actually opens the blood-brain barrier for about an hour. And so we're conducting several studies and analyses and it turns out, I can tell you, this is a very promising approach to get drugs across the blood-brain barrier.

Amanda Dee: And do you have anything else that you want to add about your research or some of the work that you've been doing in clinic?

Adam Sonabend, MD: I would just say it's very important if there's a patient out there listening to this to keep hope. It's very important also to be an active participant in clinical trials. I think it's really important for the patient wellbeing as well as for the community to not settle for the standard that we have, but try to enhance it. I think it's important to be well connected to an academic center that is offering these new treatments because the best outcomes might not be the established treatments. And we need to investigate these to keep moving the bar.

Amanda Dee: Well, thank you, Dr. Sonabend, for sharing your insights and expertise on the show. I'm sure we'll be hearing more about you and all of your research in the years to come.

Adam Sonabend, MD: Thank you. It's my pleasure. Thanks for inviting me.

Amanda Dee: If you liked listening to this episode of Breakthroughs, be sure to rate us and review us on Apple Podcasts. And you can find more episodes at feinberg.northwestern.edu.