When Sen. John McCain died on Aug. 25, the Arizona Republican was hailed for his courage and tenacity as a POW during the Vietnam War, political battles in the decades since, and his fight against the brain cancer that took his life.
It was a glioblastoma, one of the most difficult brain tumors to treat, and one of the deadliest.
Researchers are working to unlock its secrets. Among them are Donald M. O'Rourke, the John Templeton Jr., M.D associate professor in the Department of Neurosurgery at the University of Pennsylvania's Perelman School of Medicine.
At his O'Rourke Lab in the Abramson Cancer Center, he and other researchers are dedicated to finding better treatment options for glioblastoma. One of the promising areas involves T cells, the workhorses of the immune system. In a Penn-pioneered treatment already in use for childhood leukemia, T cells can be extracted from a patient, altered genetically to increase their ability to fight the cancer, and then returned to the body.
Will it work for glioblastoma? We recently spoke with O'Rourke about his research and his reasons for hope.
What is glioblastoma and why is it so difficult to treat?
It's called a primary brain tumor, as distinguished from a metastatic tumor. It's a tumor that started in the brain, rather than traveling to the brain from a different part of the body. There's a spectrum of these tumors. Glioblastoma is the most common primary brain tumor in adults.
It has a high level of invasion, of blood vessel recruitment, and atypical cellular architecture – its cells are dividing faster and have an atypical configuration. The important thing about why this is challenging and why this is different from other tumors is its capacity to be invasive in the brain. It doesn't grow in the form of a sphere, or a nodule. It infiltrates normal brain tissue. It sort of mixes and integrates with that tissue. That makes the neurological component of this tumor difficult. It also makes surgical and radiation treatment challenging. It's a challenge to separate the normal tissue from the abnormal tissue. In contrast, a tumor that metastasizes to the brain from, say, a breast or a lung, doesn't grow the way a glioblastoma does. Those tumors grow in a more obviously separable way. They're easier to treat surgically, more easily targeted by radiation therapy.
This is simplifying things, but the capacity for a glioblastoma to infiltrate with the normal brain is the main aspect making treatment difficult.
What is typical treatment after surgery?
The standard-of-care treatment for this is an oral chemotherapy regimen with radiation therapy. After radiation therapy, oral therapy is continued for six months. That's a standard that was established in 2005, so it's getting a bit old now. There are no standards for the experimental care we like to provide at Penn. We're investigating new combinations in order to improve the survival. Right now, survival is in the range of 15-18 months, as an average. But glioblastoma is not thought to be the same from one patient to the next. The survival can be very different.
Is there anything on the horizon that would make glioblastoma less of a death sentence?
At Penn, we're part of the immunotherapy group, a world-leading group in terms of using T-cell therapy, which has already shown significant benefits in pediatric leukemia. We're adopting some of those approaches to treat glioblastoma. We have done one clinical trial and will be initiating several new trials in the upcoming year.
I think there's a consensus in the field that using the immune system to moderate glioblastoma will be an effective strategy. It's very complex. The components of the immune system are complex. There are various ways to manipulate that immune response. Right now, no one knows what the best one is. For the next few years, we'll be working on discovering the most effective combinations for immunotherapy for glioblastoma. We don't know what the best strategy will be ultimately, but we believe we've identified a strategy that will be more effective. One of the approaches we have been using is engineering a patient's T cells and then intravenously infusing them — like a pint of blood. That may change. We may be putting those T cells directly into the brain. That's a big area of potential work.
The best examples of the use of immunotherapy are in pediatric leukemia and adult melanoma. We're borrowing some of that and making some adjustments. We have quite a bit of work to do in this area. But I do think people feel this is a promising — maybe the most promising — strategy that the field has identified over the last several decades.
But clinical trial work moves slowly. The general public doesn't have a real sense of the regulatory hurdles. I fully understand that people want progress. I think there's been pretty remarkable scientific progress — dramatic progress — but it hasn't translated to clinical application. I hope that in the next three to five years we'll have a better idea of whether we've identified the right combinations.
Are there other advances?
Yes. The standard elements of care — surgery, chemotherapy and radiation — have improved over the last several years, mainly with advances in MRI technology. Our MRI navigation systems for surgery are better. Our options for focused radiation are better. That's always going on. At the same time, the options for experimental care will be improving.
What reassurance can you give patients?
What I tell patients is, first, that they need to be treated at a major center. Second, they have to have the best standard of care. And they have to have experimental care. The level of progress is not linear; it's exponential. We believe that even in the next 12 months there will be changes to care. My message is to have faith in the scientific process.
There's nothing I can tell them to take away the life-altering diagnosis. It's a game-changer for a functional person and their family. So they have to latch on to hope. I think we're going to deliver on this hope. But it's not going to be immediate. It's going to be in that three- to five-year window.
It's not because people aren't trying. There's an enormous team that's been mobilized at the Abramson Center. But the process of clinical trial work and regulatory hurdles to allow treatments to move forward has an inherent slowness. It takes time. The slow pace of discovery and innovation is not a lack of motivation.