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.
