Brain Cancer Awareness Month: Challenges and Innovations in Treatment

Theodore Schwartz, MD

Treating brain tumors faces unique challenges due to the protective blood-brain barrier which limits the effectiveness of conventional chemotherapy and immune responses, often making the landscape of brain cancer treatment complex.

While chemotherapy like temozolomide remains a standard treatment for patients with glioblastoma multiforme (GBM), its efficacy is limited. According to Theodore Schwartz, MD, this is especially true against the frequently mutating and heterogeneous nature of GBM cells.

Experimental therapies work to target specific mutations, and some have shown particular promise in this space; however, none have yielded significant breakthroughs due to their variable effectiveness and the toxicities observed. While antitumor vaccines and other gene therapies have also been explored, their successes have been limited.

To overcome the blood-brain barrier, Schwartz, neurosurgeon at Weill Cornell Medicine and NewYork-Presbyterian Hospital, emphasized the potential of various approaches, including focused ultrasound, photodynamic therapy, and electrical stimulation. Each of these methods aim to open up the blood-brain barrier in a selective manner or target tumor cells while minimizing the damage to healthy brain tissue. Despite ongoing challenges, combined approaches to therapy have shown potential as well, offering more hope and improved outcomes in the future.

“I think it is important for clinicians who take care of brain tumors to go out, talk about them, be public, and express not only how important it is to come up with new therapies, but how important it is for people in the community to identify when these tumors arise, because we have to find them. The earlier we find them, the better,” Schwartz said in an interview with Targeted Oncology^TM.

In the interview for Brain Cancer Awareness Month, Schwartz discussed the challenges of targeting brain tumors, emerging therapies, and strategies to overcome the blood-brain barrier.

Targeted Oncology: Can you discuss the current brain cancer treatment landscape?

Schwartz: What is important to understand about brain cancer that makes it different from every other cancer is that the brain is a unique environment in that cancers that arise in the brain are protected from the rest of the body by something called the blood-brain barrier. The reason that is important is that if you give chemotherapy in the body through an IV, and you hope it is going to get to your cancer, or any kind of treatment, if the bloodstream cannot deliver treatment to the cancer because it is blocked off, whatever you give is not going to work as well. The brain is somewhat of a protected site, although there is the ability for stuff to get through the blood-brain barrier. So, some of the therapies we give do actually cross.

The other thing that is important to know is that the immune cells that fight off most cancers in the body also cannot get into the brain in the same way that they can get into the rest of the body because of this blood-brain barrier. It is what we call an immunologically privileged site. Some of the white blood cells can get in there, some of these T cells that we want to activate can get in there. Although it is privileged, it is not totally isolated, so there is an opportunity there.

The other important thing about brain tumors is that they invade into the brain, and they can invade far into the brain, even to the other hemisphere of the brain. If you do surgery to take out a tumor, we really have only taken out 98% of the tumor, and the rest of the tumor is impossible for us to track down because it is invaded through so much of the brain. The other important thing to know is that brain tumors have a way of downregulating the whole body's immune system. What the brain tumor does to protect itself is it basically will suppress the body's immune response so that any therapy that normally enhances the tumor is fighting against it.

In your experience, what are the most promising treatment approaches for brain cancer?

There are different classes of treatments that we give for brain tumors, and the most obvious is just chemotherapy. We found out that for the most part, chemotherapies do not work that well. There is 1 chemotherapy that we use most often, which is called temozolomide. That has been shown in a randomized trial to work well against glioblastoma multiforme in addition to radiation, and that is the standard of care. It particularly works well if there is a specific mutation in the glioblastoma cells. But once you get past those sort of general chemotherapy things, there are then all these experimental trials that have been going on with different options.

We can divide those into wells and give certain drugs that target, specifically, glioblastoma cells. There have been drugs that target specific mutations within those cells, and none of those have worked that well. They target things like EGFR or BRAF V600, etc, and we have given all these different drugs. None of them have been a home run. They have kind of worked against some of the cells, but GBM is constantly mutating, and they are heterogeneous. So, if we find a drug that treats some of the cells of a GBM, well, we kill off those and then the rest of the cells just keep growing. That is the problem.

The other group of treatments we have are immune checkpoint inhibitors, and those are basically brakes on the immune system that prevents us from developing autoimmune diseases because we do not want to have our body attack ourselves. Tumors can basically co-opt that system to avoid detection. The idea is if we can inhibit that, we can activate the immune system and sort of counter the tumors, deactivating the immune system. These are anti-CTLA-4 drugs, and anti-PD-(L)1 drugs, and those have been given before surgery, after surgery, and have had some efficacy, but nothing that has been that kind of big result that we have been hoping for. They have a lot of [adverse] effects, unfortunately, but the good news is there may be some subgroups of GBM that do respond to these, but it is not something that we can just give to everybody. We are trying to figure out who they work better on and who they work worse on.

3D illustration of human brain anatomy: © PIC4U - stock.adobe.com

Then there is this whole class of vaccines, antitumor vaccines, that we are trying. The idea of an antitumor vaccine is that we want to inject some chemical that is on the surface of a GBM so that the immune system starts to respond to that. We have tried vaccines againstEGFR and other things. Some of them have been promising, and it worked in a subgroup of patients, but it is the same idea since we are only targeting 1 antigen on the GBM. We may just be killing off 1 subpopulation of the GBM cells, then the rest of them just keep growing because of this sort of heterogeneity of the cells and the diversity of the cells that makes it so hard to treat. The other thing that makes it hard to treat is they are these glioma stem cells, and these so if you kill off a lot of the main cells of glioma, we get the stem cells that just keep dividing. Those stem cells will repopulate the tumor, so we need something that actually targets those stem cells as well.

We also do sort of gene therapy and what is called viral oncolytics, where we can create a virus that targets glioma cells or viruses that carry something that we then give to kill the cells. Those have shown some promise; there have been 20 of them, at least, that have been tried, and none of them have been a home run. There is another class of drugs called [chimeric antigen receptor (CAR)] T-cell therapy, and a lot of these therapies are great for lymphomas and leukemias and work well against myeloma or melanoma, for example. The idea is that we can take T cells from the blood and can modify them with a viral vector to express a certain time in what is called a chimeric antigen receptor. Those have been tried with a couple of different specific receptors; none of them have worked dramatically. Some of them show progress in a subgroup of cells, but there have not been any home runs.

Where I think there is hope and progress is combined therapy. That is what we are trying to figure out is if each of these therapies works against a subgroup of cells, how do we combine them, so that we can use 2 or 3 of these different modalities to hit the glioblastoma in different ways so that we can knock it down more permanently? Because everything we knock it down with has some efficacy. The tumor manages to overcome it because it grows and mutates so rapidly, and it is so heterogeneous that it has ways of evading the immune system. That is the difficulty of treating glioblastoma. The truth is, there is no 1 thing at the moment that is so promising that we can say, this is going to be the answer. But each of the therapies that we have tried has had some efficacy and some subgroups of tumors that the combination of 2 or 3 or 4 of them may lead to something that is more profound.

How can we better integrate newer therapies into existing treatment regimens?

The standard of care, which is radiation and chemotherapy, most people come to surgery, and we now have improved the way we do surgery because we are trying to take out as much of the tumor as we possibly can. We now have a drug called 5-aminolevulinic acid that patients can drink beforehand, and it makes the tumor cells fluoresce. We can be more aggressive with our surgery, but surgery is not the answer to this problem because if a tumor is invading the part of the brain that moves the arm, we cannot just remove that part of the brain because the patient would be paralyzed or not be able to speak. We cannot keep taking out more brain, unfortunately, because then we are not winning the battle. The person you knew before no longer exists after your surgery. Once that is done...the standard of care works for a period of time. [Then], it is about enrolling patients in as many clinical trials as we can to figure out which are the subgroups of patients that respond to different therapies and trying to create new clinical trials that combine different therapeutic modalities together to try to get them to work together, essentially, to enhance each other, and knock out different subgroups of these heterogeneous tumor cells.

What are some of the current strategies for overcoming the blood-brain barrier to deliver medications to brain tumors?

The blood-brain barrier is an issue, and there are many different ways to do it. We kind of divide those into chemical ways, mechanical ways, optical ways. We can give certain drugs, put a mannitol in an artery going into the brain in a particular area to try to open up that blood-brain barrier, then shoot in whatever drug. We can shine laser light; we have a treatment called laser interstitial thermal therapy, [and] that is an ablative therapy, but also does break down the blood-brain barrier and may help combining a laser therapy with some sort of a systemic therapy. Then there are electrical ways of doing it, where you can electrically stimulate with electrodes, or what is called transcutaneous spinal direct current stimulation.

One of the more exciting things going on is sort of a new technology. The focused ultrasound works as a patient's head goes into a device, and there are like 1000 different ultrasound transducers that send ultrasound waves into the brain, and they can focus all of those ultrasound waves at a point or an area. When [done] at a very high frequency, it can cause damage to the brain. But if [done] at a lower frequency, it can open up the blood-brain barrier. The idea might be that you have a patient with an IV in their arm, nothing's going in the IV. We bring them in the focused ultrasound, open up the area of the tumor, maybe even in the surrounding brain, give an IV therapy for a neutral arterial therapy, and the blood-brain barrier is now open. It selectively goes into that area of the brain and helps treat the tumor specifically in the areas around the tumor. But the blood-brain barrier then helps protect the rest of the brain, because it can break it down just in a particular location. All of these trials are ongoing, using focused ultrasound by itself and in combination with other systemic therapies to try to treat these brain tumors and then again, combining that with multimodality therapy with multiple different treatment types could lead to some breakthroughs coming down the line.

How can we better account for tumor heterogeneity when designing treatment plans for patients with brain cancer?

That has to do with designing therapies where, because tumors are so heterogeneous, if we are going to create a vaccine, we want to take a specimen from the tumor and break it up in some way so that all of the heterogeneous antigens from the tumor are exposed to the dendritic cells that can then create T cells that can attack the tumor. It is about creating some kind of a personalized vaccine that uses the patient's own tumor, which is going to be unique and diverse to create your therapy. We have the ability to do that. We can sequence these tumors and we can create therapies.

Are there any exciting brain trials you can discuss that are ongoing?

There is 1 trial that we have participated in where we basically take out the glioma, the GBM, and then send it to the company. They take it and they expose it to what is called an antisense oligonucleotide, which is against a specific receptor, and then they kill the tumor with radiation. Then, they implant that dead tumor that now has sort of exploded and released all its antigens into the abdomen. The patient's body sees these foreign antigens emerging from these little chambers that are implanted in the sort of near the stomach muscles, and then creates immune response T cells that then can travel up to the tumor, go through the leaky blood-brain barrier that is there, and hopefully, treat those cells. That is a trial that is ongoing, an interesting new trial, and even if that 1 person per se does not work, the idea of implanting these chambers with antigen and creating sort of your own vaccine within your own body against your own tumor is exciting. Ideas like that are what we need to move the field forward.

Are there any emerging technologies that hold promise for addressing some of the challenges that are seen in the brain cancer space?

I talked a little bit about focused ultrasound, and I think that is one that people are excited about. There is also the concept of doing photodynamic therapy, which is the idea of once we have removed a tumor and all that is left is sort of microscopic remnants around the cavity, if we can give a drug that goes into those cells and makes them sensitive to certain wavelengths of light, we can then just shine light in the cavity and kill those cells. That has been effective in other tumors in the body and is being explored in glioblastoma as well. Obviously, it is not going to take care of the tumor cells that are 3, 4, 5 cm away, so that becomes more challenging.

How can we continue to raise awareness among clinicians and oncologists about early signs and symptoms of brain cancer?

I think it is important for clinicians who take care of brain tumors to go out, talk about them, be public, and express not only how important it is to come up with new therapies, but how important it is for people in the community to identify when these tumors arise, because we have to find them. The earlier we find them, the better. The younger patients are when we treat these tumors, the more effective that therapy is. The smaller the tumors are, the better they do.

I recently wrote a book called Gray Matters. It is coming out in August for the public about brain surgery, what it is like to be a brain surgeon, and how to make decisions. But a lot of it talks about brain cancer and about how, as a clinician, we deal with patients who come to us with malignant brain tumors. How do we talk to them? How do we break the news to them? What are we thinking about when we're operating on them? Part of the reason I wrote the book was to raise public awareness, experience, and understanding of these brain tumors to help the general public cope with them.

What advice do you have for other oncologists regarding brain cancer treatment and awareness?

Just the importance of keeping yourself up to date and educated on the latest clinical trials. When I see a new patient with a malignant brain tumor, they will ask me about clinical trials, they will ask me about where they should go. I give them a couple bits of advice. One is that they should get more than 1 opinion. I think it is important because this is such a difficult cancer to treat that you want the patient to feel like we have not left a stone unturned. I do direct them to clinical trials web pages that describe what is ongoing so they can educate themselves. I make myself available to discuss the clinical trials with the patients so they understand what they entail.

I also make it clear that it is not like there is a magic bullet out there that exists right now that they are going to miss out on because if there was a cure for these tumors, we would all be doing it as soon as we knew about it. They should not upend their lives too much to seek out experimental clinical trials, because many of them do not work and it is important for them to preserve their quality of life for as long as possible and be with their family and friends for as long as possible and use that time that they have as best they can until we have more effective therapies.