From the day he arrived at UAB in 1993, David Curiel, Ph.D., director of UAB’s Division of Human Gene Therapy, has found an eager research partner in Ronald Alvarez, M.D.

Over the years, Drs. Curiel and Alvarez, head of the Division of Obstetrics and Gynecology, have collaborated on testing a variety of cancer treatments involving everything from single-chain antibodies to “suicide genes,” all in the name of “bench-to-bedside” research that pays tangible benefits for the world’s health. “I’ve been bugging him for a long time,” says Dr. Alvarez with a grin.

Since the late 1990s, the two researchers have focused intently on virotherapy, modifying certain kinds of viruses to transform them into cancer killers. That work has resulted in a new therapy, one that entered clinical trials this summer, that actually makes a specially designed adenovirus many times more infectious and powerful—all to combat ovarian cancer, the fifth leading cause of cancer-related death in women.

Creating a Cancer Fighter
Much of UAB’s virotherapy research has focused on conditionally replicative viruses—primarily herpes, reovirus, and adenovirus—which are basically “programmed” to infect and replicate only in cancer cells without harming the body’s healthy cells. “The problem with all of this is that even though they are specifically targeted, their overall effectiveness hasn’t been great,” Dr. Curiel explains. “Their antitumor response hasn’t been what we would have hoped—they don’t work in humans as well as they worked in experimental models.”

In particular, conditionally replicative adenovirus (CRAd), which can cause respiratory illness, was an effective killer of cancer cells in animal models, but had trouble first breaking into those cells. The reason, Dr. Curiel says, is that human tumor cells are deficient in a receptor mechanism called CAR. Getting CRAds to infect cancer cells through a pathway other than CAR became a new research mission for Drs. Curiel and Alvarez.

Eventually the research team discovered that incorporating a small peptide, or amino acid chain, into the virus shell greatly improved the virus’s ability to infect cancer cells—without requiring CAR as a catalyst. “We think of viruses as being fully evolved, minimalist structures,” Dr. Curiel says, “but we found that we could manipulate [the adenovirus] much more radically than we thought. You would think, because of the evolutionary model, that God made the most efficient virus possible, but we found that the virus was now 10,000 times more potent.”

At the same time, UAB’s researchers were working with a group at the M.D. Anderson Cancer Center at the University of Texas who had invented a CRAd agent called Delta-24. UAB team members asked if they could modify Delta-24 with their newly discovered peptide, and sure enough, the modified Delta-24—now known as Delta-24-RGD—became dramatically more effective in treating a rat-glioma model Curiel calls the “gold standard” for glioma research.

The collaboration then set about tackling two cancers at once. M.D. Anderson and its partners at the Free University of Amsterdam would test Delta-24-RGD against brain glioma, while Dr. Alvarez began testing it in mouse models of ovarian cancer. Once again, Dr. Curiel says, the agent demonstrated dramatically improved responses.

A Resounding Vote of Confidence
Drs. Curiel and Alvarez still had huge obstacles to navigate, however—mainly what Alvarez calls an “alphabet soup” of regulatory agencies and committees. The biggest hurdle they anticipated was the National Institutes of Health’s (NIH) Recombinant Activities Committee (RAC), composed of some of the country’s most senior scientists, ethicists and patient advocates and charged with granting (or denying) approval for any radically new genetic treatment. Delta-24-RGD, the first “tropism-modified” virus to be used in humans, definitely fit that category.

But Drs. Curiel and Alvarez began strategizing early. “We didn’t just present ourselves at the doorstep of the RAC,” Dr. Curiel says. “Years before, we presented our idea to the Food and Drug Administration (FDA), solicited their input, and gained their counsel.” When they finally went before the RAC, they received a virtually unprecedented unanimous recommendation. The 17-0 vote was “surprising and pleasing, and extremely validating,” adds Dr. Curiel.

That approval opened the doors to a wealth of NIH funding, including a mechanism called RAID (Rapid Access to Interventional Development), that directly supported Delta-24-RGD research. And in March, Drs. Curiel and Alvarez went back to the FDA, receiving its official approval. The clinical trial officially launched June 1.

Cautious Optimism for a Cancer Killer
The trial is starting small, says Dr. Alvarez. “It’s a phase 1 trial, so we put three patients on a specific dose—a daily-times-three treatment. If they do OK with it, we’ll put another three patients on a slightly higher dose, then another three patients at a higher dose, and so on, up to as many as seven dosing cohorts—it really depends on how patients tolerate it.”

“Deliberate” would be one way to describe progress in the larger fight against ovarian cancer; “slow” would be another. Because ovarian cancer is difficult to screen for, most patients aren’t diagnosed until advanced stages; over the past 20 years, doctors have been able to increase the life span of such patients from 12 to 18 months to three to five years, but the overall survival rate has improved little. With that in mind, Dr. Alvarez says that he and Dr. Curiel don’t expect the new treatment to be an instant “home run”—rather, they see it as an important step in an ongoing process.

“Once we figure out the dose where most patients will tolerate it, and we have some studies that will tell us whether it got into the cells and is replicating—whether there is any evidence of a clinical effect—we don’t know how much further it will go. This is really a whole new treatment paradigm,” explains Dr. Alvarez. “But my hope is that in the future, we’ll be able to make a virus—if not this virus, then another like it—that will not only put this cancer in remission, but also keep it in remission.”