Novel Treatments in Glioblastoma: Looking Ahead

Transcript:Steven A. Toms, MD: What is the future of a device like Optune? It seems to be a fairly basic mechanism in cancer that may be used in other areas. Certainly, I know that there are trials going on in Europe right now for lung, ovarian, and pancreatic cancer. The data from that is not yet available, so I’m not sure how it will work on other systemic cancers. As far as the brain goes, there are certainly a couple areas that I, as a neurosurgical oncologist, think this device may be useful.

One of the toughest nuts to crack in neurosurgical oncology is something called a malignant meningioma. Most meningiomas are benign, but there’s a small subset—we probably see two or three per year at a practice like ours—where you have a recurrent tumor that is very, very aggressive. Meningiomas resisted all types of repeat radiation and chemotherapy thus far, and I know there’s a trial that Phillip H. Gutin has started at Memorial Sloan Kettering to look at this device in malignant meningioma.

In addition, I’ve heard of plans for using this device in metastatic disease. There are going to be some limitations with that because the field strength does not get very high in the posterior fossa, around the cerebellum and brain stem. If a patient has metastases in that area, this device may not work terribly well in its current design, but there are some thoughts that this may be useful in patients with diffused metastatic disease in addition to their chemotherapy—and, most commonly, in radiation therapy such as Gamma Knife for stereotactic radiosurgery for metastatic disease. I believe there are plans to open that trial somewhere in the next year or so in a number of centers internationally, so more to come on that.

One of the most exciting areas of development in glioblastoma that I think we’ll be seeing progress in the next five to 10 years includes the immune-modulatory therapies. When I started my research about 25 years ago, we were mostly looking at monoclonal antibodies or surface proteins that might be different. Although monoclonal antibodies haven’t panned out, a number of things in immune-modulatory therapy have.

What we’ve seen is a number of different peptides targeting items such as the EGFRvIII receptor. A lot of that work started many years ago when Darrell D. Bigner was at Duke 30 years ago. It has continued to their current chairman, John Sampson. They were both looking at vaccine trials as well as cellular immunotherapy.

There’s a large trial going on by a colleague of ours, Linda Liau, at UCLA, who started what’s called the DCVax trial, which is the dendritic cell vaccine where the tumor is taken out, the peptides are lysed in the laboratory and put together with the patient’s own dendritic cells, and then given back in vaccine form. Linda’s had some success with that at UCLA, and there’s a larger trial underway right now.

One of the biggest developments lately has been in the in the immune-modulatory checkpoint inhibitors, such as the PD-1 inhibitors. Virtually all of the big pharmaceutical companies are working on different checkpoint inhibitors now. And we’ve seen good results in a number of cancers, such as melanoma and lung cancer.

In addition, we’ve see some early preliminary results in recurrent glioblastoma with these checkpoint inhibitors, and I think it bears watching in the next five to 10 years to see how these immune-modulatory therapies come out. We’ll also be very curious to see what happens when we combine the immune-modulatory therapies—whether they be vaccines or checkpoint inhibitors—with things like the Optune device.

If you think about the mechanism of how each of these works, you’d think they probably wouldn’t interfere with each other, and they may even be synergistic in some ways. But obviously, what we think is going to work in a petri dish or a mouse doesn’t always work in a human being. So we’re going to have to start combining these agents to see how they work. But the future looks very bright for glioblastoma. I often tell my patients that the era for glioblastoma now reminds me of the era of pediatric lymphoma and leukemia back in the 70s where we went from virtually every patient dying to starting to see our first big increase in survival and hopefully soon getting to our first cures of this terrible disease.

Some of the other hot topics that have been out there in the years include convection-enhanced delivery—which is a way to put catheters in their brains to deliver therapy. That hasn’t panned out terribly well in the two trials that were started about 10 years ago, but it’s seeing resurgence. So, more to come on that and how to get drugs in beyond the blood-brain barrier.

In addition, I’ve done some work in nanotherapeutics. Often, what we’re seeing with nanotechnology are ways to deliver either a drug or gene that may get them into cells—and sometimes you see a bit of an immune response to the delivery device—being the nanotechnology that may augment the therapeutics that are delivered in glioblastoma.

Finally, the last big topic is gene therapy and viral oncolytic therapy. These have been around and targeted for glioblastoma for about 20 years, and we’ve seen some early initial publicity with the poliovirus trial down at Duke. And what we’re seeing with both of these types of therapies is that by putting genes into the tumor cells or letting viruses deliver genes or try and lyse the cells themselves, we’re getting an expression of new antigens that allows the body’s immune system to identify that these cells are foreign to the body and helps attack. I think these are really just a tweak on the immune-modulatory therapy going forward. And they’re getting some new life as the immune-modulatory therapy’s moving forward.

In summary, it’s a really exciting time for glioblastoma between the tumor treating fields and the immune-modulatory agents, and so we’re revising some of the old ideas that have been out there for the last 25 or 30 years on glioblastoma therapy. Although it’s never a good time to have a glioblastoma, the prognosis is not quite as grim now as it was when I started my career 25 years ago. My hope is that by the time I’m ready to retire, that we’ll have made some significant progress on this disease.

Transcript Edited for Clarity