Gene therapy experiment at U-M
Researchers’ 15-year quest for a brain-tumor cure finally reaches human trials
TEDxUofM speakers Maria Castro and Pedro Lowenstein, doctors at U-M, have embarked on an amazing journey to cure brain tumors through genetic engineering. They’ve graciously allowed The Ann to follow their work over the next few months, giving readers an inside look at their successes and failures and introducing some of the patients who have volunteered to participate in upcoming human trials. If you have specific questions for the doctors, send an email to firstname.lastname@example.org.
By Jud Branam
Walking a visitor through the Castro-Lowenstein Laboratory, office manager Molly Dahlgren points out some of the more interesting devices used to conduct gene-therapy experiments. Here’s a machine that extends the useful life of lab rats by facilitating fluorescent examination, there’s a computerized scanner for precise tracking of tumors and there’s a “brain sectioning cell-something.”
She laughs, then shrugs and continues the tour. Dahlgren’s to be forgiven for not knowing each piece of apparatus by name. After all, it is brain surgery.
This triangular suite of a dozen offices and labs, four floors up in the maze that is the University of Michigan Medical Center’s research campus, is home to an effort that offers hope of a major new weapon in the fight against deadly brain tumors. An affable yet intense pair of researchers, Maria Castro and Pedro Lowenstein, have spent the last 15 years in pursuit of what she calls “the ultimate frontier” of cancer research: gene therapy that can enable the body to combat brain tumors.
The couple, both Argentinians who met and married in the U.S. and have worked in labs from California to England, are about to embark on the first phase of clinical human trials of their unique approach, which introduces genetic changes into tumorous cells to kill the cancer cells and prevent their regeneration.
A dread disease
Brain tumors kill more than 13,000 Americans each year, according to the National Cancer Institute. Glioblastoma multiforme is the most common and deadliest of adult primary brain tumors, about 20 percent of cases. The average age at diagnosis is 64, and men are more likely candidates than women for the diagnosis.
Because of GBM’s quick growth and spread, patients live on average less than two years after being diagnosed. Virtually none make it five years. This survival rate has improved over recent years only slowly despite advances in chemotherapy and cancer drugs. This bleak scenario has a couple of advantages from a clinical perspective — it makes the disease a better prospect for untried alternative approaches and it will yield results comparatively quickly, especially in the safety trial.
“Because the disease is so deadly, that poses a huge disadvantage for patients,” Castro says. “But it’s an advantage for clinical trials because we will know the results — in clinical trial time — relatively quickly.”
How gene therapy works
The technology itself is the stuff of science fiction; think of the old movie “Fantastic Voyage.” Instead of a tiny submarine traversing the body, our vessel is a highly modified virus which also has the ability to pass along payloads. The idea is to introduce DNA to inhibit tumor growth, kill the cells that feed the tumor or induce some other beneficial action.
Two such treated viruses, known as vectors, are deployed in combination in the Castro/Lowenstein approach. One kills tumor cells on contact, the other incites the body to make more cells to hunt down and kill other cancer cells. “It’s the first ever trial in human brain tumors that uses two different adenoviral vectors. It’s really a first for mankind,” said Lowenstein.
Gene therapy has shown promise in fighting several diseases and cancers. Bolstered genetics have restored sight in congenitally blind patients and helped young patients overcome severe combined immunodeficiency, sometimes referred to as the “bubble boy disease.” British researchers recently reported success against relapsed leukemia through genetic treatments. And last November, the European Union gave market approval to Glybera, a genetic-therapy drug for a rare metabolic disease.
Though wildly expensive and obscure from a market perspective, the Glybera approval marks “a huge step forward for the field because it’s the first time a genetic medicine has been licensed,” Len Seymour, a professor of gene therapy at Oxford University told The Wall Street Journal. “It begins to exemplify what genetically coded medicines can do.”
This momentum comes after a fallow period for the gene therapy, caused by high-profile failures when a clinical trial patient died in 1999 and when several patients contracted leukemia in 2003.
Lowenstein says the fact that gene therapy was a new and unproven area of medicine resulted in a very high level of scrutiny and review of all the trials, and subsequently a massive amount of media and public reaction when the clinical trial death occurred. By contrast, thousands of patients die during drug trials each year, and other leading-edge work such as stem-cell research has resulted in deaths without the same level of attention or consternation.
The entire field was set back a decade, he says.
But now, Castro said, “The tides are changing. It’s gaining consensus among the population and I think people are more accepting of the idea.”
U-M neurosurgeon Oren Sagher will inject the gene therapy into the margins around tumor removal areas in patients who take part in the clinical trial.
“As far as neurosurgery is concerned, it’s a quantum leap,” Sagher said of the procedure. “Almost all cures for cancer are related to the body’s ability to reject the cancer cells. The problem is that the brain is an immune-privileged organ, so it’s hard to trigger that immune response. This allows us to do that.
“And it uses genetic engineering, but we’re not trying to inject genes into healthy cells, we’re trying to inject genes into the tumor cells.”
‘The Ann Arbor way’
The promise of Castro and Lowenstein’s work is evident from the competition among research institutions to employ them. After their work at the University of Manchester in the UK gained notice with a 1999 medical journal article, they were recruited by Cedars-Sinai Medical Center in Los Angeles. More publications and years of successful pre-clinical research ensued, after which they were wooed to move their operation to Ann Arbor. It was during their transitional period toward U-M that they received approval for the clinical trial.
“U-M just made us a fabulous offer to come,” Lowenstein said. “It’s a big academic institution, one of the flagship universities in the country and they put together a very attractive package for us to move.”
Karin Muraszko, chair of the U-M Department of Neurosurgery, led the couple’s recruitment, she said, to bring more research strength to a department deep in high-quality clinicians.
From a logistical standpoint, U-M offers all the elements needed for the trials, not least of which is proper storage and handling of the vector viruses that were created at a National Institutes of Health-certified lab at Baylor College of Medicine before recent shipment to Ann Arbor.
“It’s critical that everything’s in the same place,” Castro says. “The University of Michigan is one of a handful of institutions in the country where the logistics of this is possible. We have here the two of us, who invented the therapy and created the technology, we have the Human Applications Laboratory that can house that vector to be tested in patients, we have the pharmacy that’s going to load the vectors into syringes, and we have the neurosurgical team which is outstanding, which is going to be able to do the surgery and deliver the therapy.
“Very few institutions have all those things in place under the same roof.”
The move also appealed to both doctors on a personal level, though for different reasons. Castro prizes Ann Arbor’s diverse and funky culture, saying that she saw men wearing skirts as part of some or other community observation when she was in town for an interview. “I said, this is our town,” she recalls with a laugh. “I knew I could live here.”
Lowenstein agrees, but says his passion stays centered on campus. That’s because in addition to being an MD, Ph.D. and tenured professor, he’s an undergraduate math major. “Math is beautiful,” he says, speaking fondly of his fascination with the concept of multiple infinities and the challenge of learning calculus decades after high school.
Indeed, Ann Arbor’s mix of liberal academia, research savvy and community-focused capitalism fits well with the couple’s vision for bringing their approach to market. Rather than teaming with a drug company to fund the work, the team uses a combination of grant funding and philanthropy to keep the lights on. If, after all the trials, this method proves effective and comes into use, the couple plans to create a nonprofit company to make it broadly available and to expand and grow.
“It’s a different approach to doing things that we’ve chosen. The Ann Arbor way,” Castro says. “I think we’re in the proper location to do it, as opposed to Palo Alto. It’s an ethical way to do business.”
The couple enjoyed a coming-out party of sorts by presenting at the recent TedxUofM event, an experience that Castro called “phenomenal. It brought together minds from all walks of life, and that’s when extraordinary things can happen,” she recalled. “Diversity rules in my mind — chemists, historians, business people all bring great things to the table.”
Since the event, they’ve received numerous contacts and inquiries from would-be employees and partners. “It’s like a multiplying effect.”
Long road to approval
Their pioneering work in gene therapy for brain cancer has recently been approved for human testing by the FDA. Next, an 18-patient, Phase I clinical trial will commence at U-M, likely within the next 60 days.
Phase I trials are known as “safety trials,” since their purpose is to establish that the treatment is safe for patients. The team is allowed to recruit one patient per month, so the first phase figures to take about three and a half years.
Two more trials are required before a treatment is allowed into the marketplace. Phase 2 tests whether the treatment actually has a beneficial effect in fighting disease, then Phase 3 requires a larger test sample, including untreated control patients, to establish the efficacy of the treatment.
“The patients are really excited about it — we get emails and phone calls from people all over the world,” Castro said. “They really want to enroll in this treatment. If it were left to the patients’ opinion, it would have happened a lot quicker.”
Department Chair Muraszko said she is optimistic about the trial, adding that any progress in helping patients survive the tumors “will be a significant victory.”
“We don’t have long and significant five-year survivals for glioblastomas, the numbers are just miniscule,” she said.
“We hope to make it a chronic disease where you can live with it for a number of years. Unfortunately, I’ve seen many, many trials that have been successful in animals, in the petri dish and then didn’t work on humans. The only way we’ll know is to try it out with people and see how it works.”
Should the next few years play out ideally and their treatment win approval, Castro and Lowenstein already have some ideas for subsequent applications. Castro wants to attack other cancers that metastasize to the brain, such as breast, prostate, melanoma and lung cancer, while Lowenstein has other cancer treatments in the research pipeline, some involving gene therapy, some small particles. But he’s quick to caution against thinking too far ahead.
“Start with one. If you’re lucky, you’ll see the end of it and we can move on to other things.”
Big ideas, big money