Experimental Treatments Target Brain Cancer Like John McCain’s

(The Washington Post) -

When Sen. John McCain, R-Ariz., returned to work Tuesday, he seemed his tough old self, saying it would be hard to call the Senate the “world’s greatest deliberative body” with a straight face. He added he was headed home soon for treatment for the aggressive brain cancer recently discovered during surgery.

McCain hasn’t announced his medical care plans, but for most patients, the first-line treatment for glioblastoma is radiation and chemotherapy. But if the cancer recurs, as it usually does, what then?

The answer could be one of the many experimental treatments being tested in clinical trials across the country. Depending on how you count them, there are dozens or hundreds of trials, many of which are focused on immunotherapy, a new approach designed to spur the immune system to attack cancer.

For years, efforts to conquer the devastating disease have ended in disappointment. Not only have researchers struggled to find effective medicines, they face challenges getting the drugs into the brain, which is protected by the blood-brain barrier, a network of tissue and blood vessels that blocks most compounds.

“We have been working very hard but have gotten just two or three drugs approved in the last 25 years,” said John de Groot, a neuro-oncologist at MD Anderson Cancer Center in Houston.

The emergence of immunotherapy, which is helping patients with advanced melanoma and other tumors, as well as some blood cancers, is providing new avenues for research. “We are trying to somehow change the tide,” de Groot added. (McCain has a history of melanoma, but his new glioblastoma diagnosis appears to be independent of the earlier cancer.)

So far, the studies have produced tantalizing clues but no game changers. “There’s a whole lot of hope, but so far things are not as simple as we had hoped,” said Eric Holland, a neurosurgeon and director of the human biology division at Fred Hutchinson Cancer Research Center in Seattle. “There’s a ton of stuff that hasn’t worked even though it looks like it should.”

In the past year and a half, for example, two promising glioblastoma treatments failed in late-stage clinical trials: Celldex Therapeutics’ cancer vaccine and Bristol-Myers Squibb’s Opdivo, one of a new class of treatments called checkpoint inhibitors.

Researchers say they are learning from the failures. They now believe, for example, that it will take a combination of treatments to make progress against the disease. One reason: Glioblastoma tends to have subpopulations of different cancer cells that require different lines of attack.

The immunotherapy approaches include checkpoint inhibitors, genetically engineered cellular therapies, vaccines and viruses that infect and kill cancer cells. Doubling them up – or using them with radiation, chemo or other therapies – could boost their effectiveness, but also increase their potential toxicity.

Deepa Subramaniam, an oncologist at Georgetown’s Lombardi Comprehensive Cancer Center, used car metaphors to describe one such combination trial. The study involves combining Opdivo, which is designed to unleash the brakes on the immune system, with a drug called varlilumab, which acts like a gas pedal on immune cells, she said.

She added that a patient at MedStar Georgetown University Hospital whose brain cancer had returned went on the trial and has survived for a year and remains stable.

Another type of combination trial will be open to newly diagnosed patients. Researchers at the Mayo Clinic in Rochester, Minn. plan to combine Keytruda, Merck’s flagship checkpoint inhibitor (and the drug used to treat former president Jimmy Carter’s advanced melanoma) with radiation and chemo, according to ClinicalTrials.gov, the federal government’s clinical trial database. The trial is listed as opening in July in Rochester. McCain has been treated at the Mayo Clinic Hospital in Phoenix. Mayo officials declined to answer questions about the trial.

Another version of immunotherapy, called CART T-cell therapy, has shown great promise in studies involving leukemia and lymphoma and is now being tried in brain cancer. It involves extracting immune cells from patients, genetically altering them to boost their cancer-fighting abilities, and injecting them into the patient.

In recent years, researchers at Duke University Medical Center have been working on a modified, non-dangerous version of the polio virus for advanced glioblastoma. The virus is delivered via catheter directly to the tumor to kill cancer cells and promote an immune-system response.

Darell Bigner, director of Duke’s Preston Robert Tisch Brain Tumor Center, said more than five dozen patients have been treated and that about 20 percent have had “durable responses,” remaining alive after two years. He said that Duke is planning to conduct another trial that adds the chemo drug lomustine to the poliovirus treatment in hopes of boosting the response rate.

“Obviously, an 80 percent failure rate is nowhere near where we want to go, but when you see responses like this and understand the mechanisms, that’s where you can start building on things,” he said. “I’ve been doing this for 50 years, and it has been very frustrating, but I do feel now that we are making very good progress.”

The Duke results are similar to what other centers are seeing using different oncological viruses, said de Groot. “With virus therapies, it seems like a small percentage of patients have a really large benefit, but it’s not going to be a therapy that will work for all patients,” he said.

For people who get conventional treatment, the median survival is only 15 months. But while some people don’t live that long, others live much longer.

Suzanne Stone, a 62-year-old resident of Fort Worth, Texas, was diagnosed with glioblastoma two and half years ago. She was running in late 2014, she recalls, when she started feeling strange and discovered she had trouble forming words. “I thought I was having a stroke,” she said. The surgeons removed a tumor the size of a “big green olive” that turned out to be malignant.

She had the standard chemotherapy and radiation, but the tumor began growing again in 2015. She had a second operation and more chemotherapy. Through it all, she said, “I have never stopped walking and occasionally jogging,” and she completed a half marathon earlier this year.

When she heard about McCain, “My husband and I got a little bit emotional because we knew what he and his family would be going through,” she said. “My message to him is, ‘Just don’t give up.’ That’s my catchphrase.”