‘Breakthrough’ treatment boosts survival in battle with deadly brain tumor

Fred Hutch scientists report early success with novel gene therapy to attack cancer while protecting healthy cells
Charlie Burgess, Dr. Jennifer Adair and Dr. Hans-Peter Kiem
Charlie Burgess greets Dr. Jennifer Adair and Dr. Hans-Peter Kiem at Fred Hutchinson Cancer Research Center. Photo by Matt Hagen for Fred Hutch

When Charlie Burgess was diagnosed with a lethal brain tumor in 2009, his future shrank suddenly to a span of four months, maybe a year at most, according to his doctors’ grim prognoses.

He had one of the most common and aggressive types of brain cancer in adults, glioblastoma multiforme, the kind that killed U.S. Sen. Ted Kennedy within 15 months in 2009.

But five years later, the 61-year-old psychiatrist from Homer, Alaska, has no sign of the disease, thanks to a potentially game-changing treatment by scientists at the Fred Hutchinson Cancer Research Center, who found a way to prolong survival in patients who were out of other options.

“I’m amazed that I’m alive,” Burgess said in an interview last fall.

Using gene therapy and a cocktail of powerful chemotherapy drugs, Dr. Hans-Peter Kiem and Dr. Jennifer Adair have been able to boost the tolerance and effectiveness of the medications that attack the brain cancer, while also shielding healthy cells from their devastating effects.

They report Friday in the Journal of Clinical Investigation on the results of seven patients, including Burgess, who survived a median of 20 months, with a third lasting up to two years – all while fighting a disease in which less than half of patients can expect to live a year.

“I think this is very promising,” said Kiem, who expects the stem-cell protocol could be used not only with brain tumors, but also other malignant solid tumors.

That’s a view echoed by stem-cell expert Dr. Stanton Gerson at Case Western Reserve University’s comprehensive cancer center, who said he patented the concept of drug-resistant gene therapy to protect bone marrow.

“That is a breakthrough,” he said, adding a caution: “But it is early, it is seven patients.”

The Fred Hutch scientists are planning to enroll new patients in a Phase 2 clinical trial soon -- after having to suspend treatment for a year because of a shortage of a key drug, O6-benzylguanine, or O6BG.

“Frustrating. That one word pretty much sums it up,” said Adair, about the delay.

Before that, momentum was high for the scientists struggling to solve a puzzle. The top treatment for glioblastoma tumors, which affect about 12,000 to 14,000 patients in the U.S. each year, is temozolomide, or TMZ, a powerful chemotherapy drug. But in about half of all glioblastoma patients, the tumors make high levels of a certain protein, methylguanine methyltransferase, or MGMT, which makes them resistant to the TMZ.

Another drug, the O6-benzylguanine, or O6BG, can turn off the resistance, allowing TMZ to effectively target the tumors. But the combination of O6BG and TMZ also kills bone-marrow cells, a potentially deadly side-effect, Kiem said.

The challenge was to find a way to protect the blood cells from the negative effects of O6BG, while also allowing the drug to do its job sensitizing the tumor to TMZ. Kiem and Adair developed a method that inserts an engineered gene into the patient’s own cells, shielding them from the O6BG.

They found that it allowed them to use combination TMZ and O6BG more effectively to target the cancer. Most typical patients might receive one or two cycles of chemotherapy; the most previously delivered was four, Kiem said.

In Charlie Burgess’ case, he received nine chemotherapy cycles.

Today, Burgess is free of cancer. He couldn’t be reached this week for comment on the new paper because he was traveling with his wife, Elaine.

One other patient in the study remains alive; the other five died, but they still survived far longer than they would have using current standard of glioblastoma care, which includes surgery, chemotherapy and radiation, Kiem said. Moreover, those patients received less total TMZ than patients receiving standard chemotherapy, underscoring the potential for O6BG to improve the efficacy of TMZ.

Gerson, at Case Western, has pursued a similar technique to treat MGMT-resistant tumors. But he said the Hutch clinical trial is far ahead of his. Kiem and Adair said no one else has yet been able to replicate their success.

That’s likely because the Fred Hutch team also added an extra step to the treatment, conditioning the patients before giving gene-modified blood cells with an additional chemotherapy drug, carmustine, or BCNU. The drug helped the patients’ bodies accept and use the gene-modified blood cells, but also treated any residual brain tumor, Adair said.

“The gene therapy might not have worked without the conditioning,” she said.

Area neuro-oncologists have been asking for months when the trial would resume because their gliobastoma patients are desperate for alternatives, Kiem said.

The shortage of O6BG was initially sparked when the vials holding the drug were set to expire, jeopardizing the integrity of the supply.

Gerson said he negotiated with National Cancer Institute officials and the U.S. Food and Drug Administration to take over regulatory control of the remaining vials of O6BG, and to deliver supplies to the Fred Hutch team.

Fred Hutch scientists have enough of the drug to treat about 25 patients in Seattle, Adair said.

New supplies of O6BG will have to be synthesized, but the results of this new trial may make that possible. When other scientists see that there’s a way to use the drug without the side-effects, demand could skyrocket.

“One would hope that with this much of a leap that more production of benzylguanine could take place,” Gerson said. 

JoNel Aleccia is a staff writer at Fred Hutchinson Cancer Research Center. From 2008 to 2014, she was a national health reporter for NBC News and msnbc.com. Prior to that she was a reporter, editor and columnist for more than two decades at newspapers in the Northwest. Reach her at jaleccia@fredhutch.org

Solid tumors, such as those of the brain, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.

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