Can Tiny Drug Doses (and One Woman’s Fortune) Fight the Most Vicious Cancer?

Xconomy National — 

When the brain goes bad, modern medicine is often powerless to help. That’s the case for Alzheimer’s disease, where drug after drug has failed, and the only approved treatments are marginally helpful at best. The same seems increasingly clear for the most common and aggressive type of brain cancer, glioblastoma multiforme. Its origins are mysterious, its ravages swift.

Fame and fortune can’t help those stricken. Glioblastoma multiforme, or GBM as it is known, killed US Senator Ted Kennedy in 2009, then ended the life of Senator John McCain exactly nine years later, despite them having arguably the world’s best healthcare. Benjamin Ivy, who ran an investment advisory firm, died from glioblastoma in 2005 at the age of 69. But after watching Ivy succumb, his wife Catherine (pictured) is trying to make fortune count, channeling their wealth into a foundation dedicated to GBM research.

Lately, she’s been running out of patience. “I’ve been doing this for 13 years and invested $90 million,” she told Xconomy at a recent meeting in San Francisco. “There’s been nothing.”

Death from brain and nervous system cancer is relatively rare, making up about 3 percent of US cancer deaths. GBM accounts for about 15 percent of all malignant brain tumors. Median survival is little more than a year, and the five-year survival rate is in the single digits, about 5 percent. Other than surgery and radiation, a few drugs—steroids, the chemotherapy temozolomide (Temodar), and bevacizumab (Avastin)—might give patients a few extra months.

Ben Ivy’s case was particularly cruel. Out on a hike with Catherine, his first symptoms were numbness in the thumb and an odd feeling in his tongue. Six weeks after surgery to remove his tumor, he began “walking a bit wobbly and struggling with his balance,’’ as Catherine Ivy described it. That was on a Friday. By the following Monday, he was paralyzed.

“He could not walk, eat, talk, or write,” Catherine Ivy said. Ben Ivy died four months after his initial diagnosis.

“Time is our most precious commodity,” Catherine Ivy said, which is why her biggest bet to date—$25 million initially, another $25 million in the wings—is on a single medical team with a cutting-edge idea, which, if it works, would speed the search for new drugs for patients who run out of time faster than any other people with cancer.

A Series of Disappointments

Recent failures to make a dent in GBM include checkpoint inhibitors, one of pharma’s most successful types of treatment in other forms of cancer.

The Bristol-Myers Squibb (NYSE: BMY) immunotherapy nivolumab (Opdivo), approved for nine types of cancer in less than five years, has failed twice in GBM trials. Another big test of Opdivo is due to report later this year.

Other Phase 3 failures include drugs from AbbVie and Celldex.

Progress is elusive for many reasons. First, the brain is a difficult organ to study in living humans, and a lab dish is a weak approximation—more so than other cancers. “We get fooled working in the lab with brain tumors,” says Nicholas Vitanza, who treats kids and young adults with brain tumors at Seattle Children’s Hospital. “Cells grow infinitely different they would in a patient. In the brain there are multiple cell populations.”

It’s also harder to try drugs out on brain cancer. GBM grows fast inside a confined space—the skull— pushing against the brain. Attacking it can exacerbate the inflammation and other side effects, including profound behavioral changes, that the tumor is already causing. At MD Anderson Cancer Center in Houston, patients aren’t allowed to join a clinical trial if there’s a danger of “midline shift”—the brain being pushed to one side—says Amy Heimberger, a neurosurgeon who studies the interplay of brain tumors and the immune system.

GBM changes fast, too, dodging and adapting to attacks like a shape-shifting villain in a superhero movie. Early 20th century attempts to stop GBM by cutting out the side of the brain where it was growing—a hemispherectomy—were thwarted when the cancer came back on the other side.

“No tumor type is as migratory or mutational as GBM,” says Nader Sanai, a neurosurgical oncologist the Barrow Neurological Institute.

Sanai is the beneficiary of Catherine Ivy’s impatience, as well as her current largesse. On the top floor of the Barrow, tucked into a dense medical center north of downtown Phoenix, Sanai is also director of the Ivy Brain Tumor Center, which the Ben & Catherine Ivy Foundation founded in 2018 with an initial $25 million to accelerate drug development.

The centerpiece of the program is what Sanai (pictured) calls “Phase 0” studies. The idea is to give a tiny, subtherapeutic dose of a drug just before surgery to remove a tumor. Once removed, the tumor tissue is analyzed to see if the drug penetrated the blood-brain barrier, moved into the tumor, and triggered any changes. If there’s significant drug activity, the patient is moved ahead to a more traditional study—this time, with a therapeutic dose.

The program is for GBM patients who have already undergone surgery, but whose tumor has grown back.

The big trick for Sanai’s team is to find the drugs that might clear all those hurdles. Here’s how that works: Sanai and his colleagues comb through medical literature to find drugs already tested or approved in other diseases, and which seem promising for GBM and other brain tumors. When they feel confident that a drug or combination of drugs could be helpful, they start a trial and look for patients. Only one such trial has been publicized so far. The Novartis (NYSE: NVS) drug ribociclib (Kisqali), approved to treat metastatic breast cancer, seemed a good fit because it blocks tumor proteins, known as CDK4 and CDK6, that GBM cells also use to multiply.

By the end of this year, the Ivy Center group expects to have 10 programs running on various drugs, according to Sanai. He declined to disclose other drugs in use without the owners’ permission.

To match patients to a Phase 0 study, Sanai’s team analyzes their original tumors, which were surgically removed after the original diagnosis. (The Barrow Neurological Institute has plenty of patients to consider, with more than 1,200 brain tumor surgeries a year.)

If a patient looks like a match, he or she is scheduled for another surgery, this time to remove the tumor that has returned. But twenty-four hours before the operation, the patient receives the subtherapeutic drug dose. After the surgery, Sanai’s team examines the fresh excised brain tissue. Did the drugs get into the tumor? Are they having a biological effect? If the effect is eye-opening—“large-scale,” as Sanai puts it—the patient moves on to a higher dose in a more conventional study setting. If not, the patient can sign up for a different trial. Once it’s clear a drug or combination isn’t having a notable effect, for whatever reason—like not squeezing through the blood-brain barrier—the program is scrapped.

The Phase 0 study with Novartis’s ribociclib presented a more complicated picture.

When the Ivy Center team examined the surgically removed tissue, they found the drug penetrating the tumor in about half of the two dozen patients. Those patients went into a Phase 2 trial, but with no success. A few of them had yet another surgery, which showed that the GBM was adapting to the ribociclib attack by activating a different pathway, known as mTOR, to keep growing. “We can see what changed,” says Sanai. Based on that information, they’re planning a new Phase 0 with a cocktail of ribociclib and an mTOR inhibitor with new patients. Everyone in the ribociclib-only study eventually succumbed to GBM.

Sanai began the Phase 0 work in 2013 with Ivy Foundation support. It was not the first effort to try the Phase 0 approach, but “this was an opportunity for us to test the waters ourselves,” he says. The decision to push ahead led to more Ivy money, and a dedicated center with a sophisticated laboratory that makes the process faster and easier. (The research team doesn’t have to send samples away for analysis, for example.) Ivy is the sole major outside funder, with matching funds from the Barrow Institute. By using her own money exclusively, Ivy has been able to control the way the center operates. The center is managed by a limited liability corporation, not by Barrow, and uses its own legal team to get research contracts wrapped up in weeks, not months, she said.

And she’s pushing most of her chips toward Sanai and the center because she’s tired of asking academics to collaborate with each other in research consortia: “They say they’ll work together because they want the money, but then they don’t.”

She’s also tired of the egos. She says she once flew several prominent researchers to Phoenix for a meeting: “Some demanded a private jet, some spent $100 on lunch.” Now when she gives money, she specifies that a maximum of 10 percent can be spent on “indirect costs.” That is, things like lunches that are not associated directly with the research. “I would go to zero, but no one ever agrees to that,” Ivy says.

The Pros and Cons of CAR-T

CAR-T cell therapies use live immune T cells that are genetically engineered to be more efficient cancer killers. Two have been approved, both for blood-borne cancers. But they’ve made little progress in solid tumors, which mount sophisticated defenses against attack. GBM is the most sophisticated of them all.

The first glimmer of hope, however, came in 2016, when doctors at City of Hope in Duarte, CA, a suburb of Los Angeles, reported that a man with GBM had his tumor disappear after a “compassionate use” CAR-T treatment—not as part of a trial, but a Hail Mary pass for someone who would otherwise have died soon. It worked for a while. After 7.5 months, his tumor returned. But that delay of tumor progression suggested the potential for success. “It was proof of principle to me,” says Vitanza of Seattle Children’s. “It was a feasible way to deliver a medicine.”

Several research centers are working on CAR-T for brain tumors—testing the modified T cells against a range of molecular targets on cancer cells, trying different delivery routes into the brain, and calibrating various doses. (Dosing is important—and complicated—because CAR-T for brain will require multiple rounds of cells, unlike the one-time infusions approved to treat the blood cancers leukemia and lymphoma.) “We have to be smart about trial design,” says Christine Brown, who leads the brain tumor CAR-T cell research program at City of Hope.

By next year, Brown says, City of Hope would like to have CAR-T therapies with good safety records against three different GBM targets, IL13R-alpha2, HER2, and chlorotoxin, which would provide building blocks for drug combinations.

And that has the attention of Sanai. He’s talking to Brown about working together. If all goes well, the Ivy Center team could be testing a City of Hope CAR-T in 2020 or 2021. The logistics of CAR-T, however, are daunting, and have already tripped up one of the world’s biggest drug companies.

Cells need to be extracted from a patient, engineered and nurtured to grow in a special facility, then sent back quickly to the patient’s treatment center for infusion. A City of Hope manufacturing facility for CAR-T and other therapies has been on the drawing board in Phoenix, but Catherine Ivy said there have been delays. Its debut is unclear. (Through a spokesman, City of Hope officials would only say “we are exploring all options.”)

One supporter of the Ivy Phase 0 program is skeptical about including CAR-T. “The center is critical for accelerating the pipeline of GBM approaches, especially small molecules, but I don’t see it optimizing a bunch of CAR-T therapies,” says Sanjiv “Sam” Gambhir, the head of radiology at Stanford University School of Medicine in Palo Alto, CA, and an expert in early cancer detection. “I don’t see an easy way of giving low, low doses” prior to surgery, to see if the treatment yields signs of activity on the tumor tissue removed. (Sanai agrees that subtherapeutic CAR-T doses aren’t feasible, but when the time comes he’s optimistic his team can design a study to quickly answer important questions.)

Gambhir’s lab has received Ivy Foundation money, and he’s been an advisor to the foundation since its early days. He has a personal interest in GBM as well. His 16-year-old son Milan died from glioblastoma in 2015, 21 months after diagnosis and—in a harsh coincidence—several years after Gambhir and colleagues embarked upon a 10-year study of CAR-T cells that migrate to the brain in response to GBM.

Thanks to Gambhir, the Ivy Center and Stanford will collaborate on a Phase 0 test of a natural product used in ayurvedic medicine, ashwagandha, which Gambhir encountered when his son was ill and he was “desperate to do anything to help him.” Gambhir and colleagues published a study of ashwagandha (aka Withaferin A) last year.

He also would like to incorporate imaging into the Phase 0 toolkit, to help the Ivy Center staff monitor patients after treatment, and eventually earlier in the process to sort patients into different treatment arms. Gambhir and Chinese researchers last year published a study that used imaging to identify lung cancer patients who were more likely to respond to a drug that blocks a mutated cancer protein EFGR. “We haven’t done that equivalent in GBM,” says Gambhir.

There’s a lot to be done. At MD Anderson, for example, Heimberger’s colleagues are working to activate other immune cells, not just T cells, that are naturally found around brain tumors. Duke University has had early success with a modified poliovirus that stimulates an immune response against GBM.

So far 150 patients have participated in the Ivy Center Phase 0 programs, selected from 350 applicants. Sanai says it takes months of research to settle on a new drug or combination for a Phase 0 trial. But he also needs to move fast. To release the second funding tranche of $25 million, Catherine Ivy wants to see drug cocktails, and she wants to see people’s lives extended.

“If this isn’t working,” Ivy says, “we can shut it down in a day.”

Photos courtesy Ivy Brain Tumor Center.