The type of brain cancer John McCain was diagnosed with July 14, glioblastoma, is among the most difficult cancers to beat. The reasons it’s so hard to treat, as I discussed previously, include its location, its genetic diversity within and across patients, and its aggressiveness. Glioblastoma (GBM) is also among the most devastating cancers in its effects since it attacks the brain, the control center for the body’s functions and the essence of an individual’s personality. Even people who survive rarely remain the same person after their treatment.
The standard of care typically begins with the kind of surgery McCain already had, an excision of as much of the tumor as possible. Next is a combination of radiation and the chemotherapy drug Temodar. Without treatment, median survival is three months, but radiation quadruples that and Temodar adds a few more months. Many patients also receive Avastin (bevacizumab), a drug that prevents new blood vessel growth to reduce swelling. But Avastin does not extend survival; it’s a palliative measure to reduce discomfort.
After that standard regime comes any of hundreds of experimental treatments, usually through clinical trials.
“They’ve tried a lot of things and nothing’s worked,” said Eric Holland, M.D., Ph.D., director of the Human Biology Division and senior vice president at Fred Hutchinson Cancer Research Center in Seattle. “Everyone has to provide the standard of care—you can’t not give it. The question is whether there’s anything you can add to make it work better, and there’s not.”
But the perversely positive side of that reality is that researchers are willing to try pretty much anything with this cancer—and they are. Hundreds of potential therapies are in clinical trials right now, perhaps with greater diversity than seen with any other cancer.
“Because the outcomes are so bad with GBM, GBM patients are on the front line of clinical trials,” said Tom Curran, Ph.D., past president of the American Association for Cancer Research and the Donald J. Hall Eminent Scholar in pediatric research at Children’s Mercy in Kansas City. “You go into clinical trials because you don’t have hope in traditional therapy. Patients are willing to fight, willing to take the chance and take experimental therapies because they have hope, and I think John McCain is an exemplifier of that.”
Another reason so many therapies are in clinical trials is the disease’s tremendous genetic diversity.
“Because of the heterogeneity of this tumor, it’s not really one disease we’re treating,” said Linda Liau, M.D., Ph.D., interim chair of the Department of Neurosurgery and director of the Brain Tumor Program at the University of California Los Angeles School of Medicine. Liau, like the other two researchers quoted in this story, is not treating McCain and is not familiar with the specifics of his illness. But she has treated many patients with similar diagnoses and noted that glioblastoma cancers fall into three or four different subgroups.
“I do think we’re making progress in these categories for some small subgroups of patients within these categories,” she said, but scientists need to learn more about those subgroups, which increased genetic sequencing is helping to do. “As we move more toward personalized medicine in categorizing and identifying these tumors better, hopefully we’ll be able to put the right patient in the right therapies. I think there will hopefully be progress in this disease.”
Liau encourages patients with glioblastoma to participate in clinical trials because trials are the only way scientists can continue making progress. The treatments researchers are exploring in those trials can be grouped into several categories (excluding a unique "tumor-field" treatment called Optune that falls into its own category):
- Standard-of-care treatments, primarily radiation and chemotherapy, basically attempt to “break the DNA,” as Holland puts it, in all the cancer cells, though unfortunately they can harm healthy cells as well. Research into these therapies explores different dosing schemes or treatment timing for radiation, drugs that enhance radiation’s effects in only specific areas, and new or combined chemotherapy agents that may extend survival as Temodar did.
- Targeted therapies aim to cripple cancer cells by going after some shared characteristics identified in all the cells, often a specific protein or a specific genetic mutation. But their strength can also be their weakness. “These are a group of small-molecule inhibitors that target specific novel things, but they can become problematic if they’re very specific because the cell gets around them,” Holland explained.
- Drugs that target metabolism “have a lot of potential,” Holland said, but they haven’t received enough attention, in his opinion.
- Epigenetic drugs, which focus on flipping certain genes “on” or “off” (changing what the gene expresses) may hold promise particularly in treating children’s brain cancer, but it’s too early to tell. These kinds of therapies are on the cutting edge and only beginning to be explored, but they require much more understanding about glioblastoma genetics than scientists currently have.
- Immunotherapy, viral therapies and cancer vaccines are a broad category of treatments that all have the same underlying goal: beef up the immune system to help it do what it’s already designed to do—kill the bad stuff in the body. Immunotherapy includes drugs called checkpoint inhibitors that attempt to turn an immune response back on at a “checkpoint” where the tumor has turned it off. Another example is CAR T-cell therapy, in which researchers remove a patient’s T-cells, an important immune cell type in fighting disease, and engineer it to go after a specific cell type. Then they grow more of these T-cells and inject them back into the patient. “There have been some really fascinating responses to those therapies, generally speaking, but it hasn’t completely been a home run yet because it’s too specific,” Holland said. Therapies that are too specific go after only one cell type in the tumor but cannot kill other cell types in the tumor.
Viral therapies involve programming different types of viruses, such as poliovirus or herpes simplex virus, to kill only tumor cells or to draw the immune system’s attention to which cells need to be killed. (A tumor can often camouflage itself from the immune system.)
Cancer vaccines train the immune system to fight the cancer in similar ways that more familiar preventative vaccines train the immune system to fight diseases such as measles or polio. The difference is that a cancer vaccine is training the immune system after it has already encountered the disease.
“More than 95% of the time, these tumors come back in a year or two, so the goal is to prevent this tumor from coming back,” Liau said. “It all boils down to inducing the body’s immune system to recognize the tumor as foreign somehow.”
Scientists can approach cancer vaccine development in several ways. Liau is working on a dendritic cell vaccine. Dendritic cells are immune cells that recognize a foreign cell that doesn’t belong and takes a piece of it (an antigen) to show other immune cells how to identify which cells they need to attack. A dendritic cell vaccine involves removing a patient’s dendritic cells, activating them against specific tumor cell antigens in the lab, and then injecting it into the patient’s lymph nodes, the “battle stations” throughout the body.
Liau, like other scientists I spoke to, doesn’t see a future one-size-fits-all drug, especially with a disease that is so internally diverse, but she does see hope.
“I think everyone anecdotally are seeing some patients respond really well and do really well, but we don’t know how to identify those people prospectively for treatment and trials,” she said. “I do think we’re making progress in small pockets.”
Identifying those individuals who respond very well to a treatment—even if others in the trial don’t—is instructive as well, Curran said.
“Every now and again, there’s a rare occurrence of a really dramatic response in a patient, and the National Institutes of Health has recognized that these outliers are really significant,” he explained. “Even one patient responding to a specific agent could be extremely informative, so the rare patients that show really wonderful responses are teaching us.”
Curran pointed to support for cancer research at the National Institutes of Health (NIH), including from Congress members such as McCain in the past, as a vital component of improving survival odds for those with glioblastoma.
“It’s very important to understand the genetic and biological diversity of tumors because in the end, the treatment approach is likely to be very individualized,” he said. “It is highly likely that McCain will receive that kind of analysis in the off chance that there is something hidden in the genome of the tumor that uncovers an Achilles’ heel. It’s rare—you can’t bet on it—but at least you can hope on it.”
Even when progress doesn’t appear obvious based on the lack of successful therapies, each trial teaches scientists more, and past advances in cancer treatments have shown how that gradual accrual of knowledge can suddenly merge into a great stride ahead, though there’s no way to tell if that’s five or 15 or 50 years away.
“Technologically, we’ve moved significantly over the last decade,” Curran said. “We know more, and immunotherapies are offering potential treatments that we never thought could have existed in the past only because of NIH-supported research.”
McCain’s reputation as a fighter and a hero in many circles offers an apt analogy for the way scientists approach cancer research, Curran added.
“His heroic character was exemplified by one thing: not because he survived torture, not because he was captured, but because he chose not to be relieved of imprisonment until the rest of his fellow soldiers were also released,” Curran said. “That’s how we approach cancer research. It’s not about developing new treatments and therapies for rich people or for people who have access. It’s for everybody.”
