The HPV Warriors
An unlikely trio of researchers has built a vaccine that attacks the virus responsible for the No. 2 killer of womencervical cancer.
By Anne Bennett Swingle | Photographs by Keith Weller
More than 100 years ago, a young New York surgeon named William Coley came upon the peculiar case of a German immigrant with a bulging tumor in his neck. After a fourth surgery, a terrible post-operative infection set in, and for days, the patient lay near death in New York Hospital. Miraculously, the patientís immune system kicked in and the infection subsided. Even more remarkably, so did the tumor.
The case made a profound impact on Coley. Maybe, he hypothesized, the immune system could be riled with a vaccine so that it would ambush malignant cells just as though they were germs. He would spend the next several decades inoculating cancer patients with bacterial extracts (Coleyís toxins) with spotty success, but he paved the way to the brave new world of tumor immunology.
Recently the field has evolved from something of a rogue scienceófull of hopes, hype and then dashed expectationsóto one that holds real promise. Thatís because advances in molecular biology have made it possible for scientists to figure out new ways to bring about highly specific immune system attacks.
Nowhere is this new dynamism more apparent than in the big lab on the fourth floor of the new Bunting-Blaustein Cancer Research Building, where tumor immunologist Drew Pardoll is leading a team of investigators who have developed a series of genetically engineered, therapeutic vaccines against the human papilloma virus, or HPV, a sexually transmitted virus that causes practically every single case of cervical cancer.
As the latest members in a long line of Hopkins physicians who have studied cervical cancer (beginning with Richard TeLinde who led gynecology for 21 years starting in 1939), this new generation of investigators represents a serendipitous convergence of talent so dazzling that some have said that if a vaccine for the cancer-linked virus canít happen at Hopkins, it probably canít happen anywhere. But while huge hopes are riding on this work, there also are huge challenges conspiring to make this a particularly long and winding road to the clinic.
The human papilloma virus comes in more than 100 varieties, from the innocuous strains that cause the common wart to the approximately 30 types that live in the genital tract, including about 10 to 15 that can cause cancer. HPV is a persistent and stealthy invader. Because it can live in the cells of the outer skin, it eludes safe-sex practices. And since it rarely produces symptoms, few people with the virus know they have it. In fact, up to 75 to 80 percent of sexually active women worldwide are infected at some point. Most infections resolve spontaneously. A small fraction, though, develop into cervical cancer.
Cervical cancer is the number two killer of women in the world, with approximately 500,000 cases annually. Itís a disease mostly of the poor and disenfranchised, women with no access to the Pap smears that detect cervical abnormalities. Keerti Shah, a School of Public Health professor of molecular microbiology and immunology who has been investigating cervical cancer and its connection to HPV since the 1970s, led a worldwide team of researchers who recently proved that practically every single case of cervical cancer is caused by HPV
In the mid-1980s, Tzyy-Choou "T.-C." Wu, a Taiwanese gynecologist just completing a masterís in public health at Hopkins, began to train in Shahís division, studying the molecular diagnostics of HPV and gradually realizing its potential for immunotherapy. On their surfaces, HPV cells have well-defined antigens, tiny bits of protein that differentiate them from normal cells, red flags that prompt the immune system to attack. These antigens, called E6 and E7, are known quantities, a dream come true, Wu thought, for the tumor immunologist who could aim a cancer vaccine directly at them.
In 1988, just as Wu was finishing up his Ph.D. in molecular biology, Drew Pardoll returned to Hopkins after a three-year fellowship at the National Institutes of Health. Pardoll was interested in tumor immunology, a field still considered a good one to avoid. He remembers that even his advisers for his Ph.D. thesis, oncology researchers Bert Vogelstein and Donald Coffey, agreed "that I would absolutely destroy my career if I went into tumor immunology." But Pardoll likes being outside the mainstream. "The best time to go into an area is when other researchers have left it for dead," Pardoll says.
Working at the very intersection of science and philosophy, Pardoll was pondering why cancers, unlike infections, spread without alerting the immune system, thinking about how they appear as what scientists call "Self," cells that are so subtly altered they are overlooked by the immune system. How to break this tolerance, he wondered? How to alert the immune system that a tumor cell was really foreign? Pardoll had begun a series of gene therapy studies, but he didnít have what he needed most, the completely foreign, reliably expressed antigens the immune system could target.
Wu, of course, knew of HPVís potential, of E6 and E7, and so he said to Pardoll, "If youíre so interested in antigen-specific vaccines, then why arenít you working on HPV?"
"I hardly knew what HPV was," recalls Pardoll. And yet, the more he thought about it, the more sense it made. In addition to having a very well-defined tumor antigen, HPV provided an excellent opportunity to go after early stage cancers instead of the more difficult bulky tumors. Before long, Wu, encouraged by one of TeLindeís successors, Bob Kurman, began tumor immunology training with Pardoll, and the two were crafting a new generation of antigen-specific cancer vaccines.
Vaccines have been the most successful medical intervention in the history of human kind, but their success against cancer has been elusive. Cancers generally are more complicated than other diseases, and unlike a virus or a bacteria, there is no simple bag of antigens with which to make a vaccine.
Because one particular strain of papilloma virus, HPV 16, accounts for over half the cases of cervical cancer, Pardoll and Wu chose it as their target. For the first time ever, Wu developed an animal model for the progression of pre-invasive to invasive cervical cancer. (It is called "TC-1," for tissue culture number one, and T.-C.Wu can barely conceal his delight that it incorporates his first name. "Suddenly," he says cheerfully, "Iíve become famous.")
The cell line expresses the E7 antigen, which Wu and Pardoll wanted to make more visible to the immune systemís tumor-fighting white blood cells, the so-called "killer" T cells. "Imagine looking at a five-acre field," says Pardoll. "If thereís one tulip in the middle, youíre probably not going to see it. But if you now have 100,000 tulips, theyíre very easy to see."
T cells would be blind to antigen were it not for the special molecules, known as MHC molecules, on the surface of cells that can see through cell walls and detect the trespassers within. Working with Wuís mouse model, the two scientists used a special sorting signal to reroute the E7 antigen into a specific cellular compartment so that it would become more visible to the MHC molecules and subsequently to the "helper" T cells that initiate, coordinate and oversee an overall immune response.
Linking the E7 gene to the sorting signal laid the foundation for a series of approaches. The scientists then fused the E7 antigen to a substance known as a "heat-shock" protein, directly increasing the killer T cell response by at least 30-fold. They also isolated a new gene responsible for sending a co-stimulatory signal to activate the T cells. Incorporating that signal has translated into even more powerful, therapeutic vaccines.
"Building the best vaccine is kind of like an erector set," says Pardoll. "You can keep adding to it, and making it better. We could spend another 10 or 20 years building the biggest building, the best vaccine, but for all we know, we already have it. The time to do the human experiment is really now."
Connie Trimble directs the cervical dysplasia and colposcopy service, where patients with abnormal Pap smears are diagnosed with a magnifying instrument, the colposcope, and treated. In December 1997, Trimble was in her office on Harvey 3 when Pardoll paid a call. In his lab, he explained, he had a whole set of vaccines against HPV antigens under development. For clinical trials, he needed what she hadópatients with genital papilloma viruses who might benefit from these novel vaccines.
Trimble was instantly intrigued. Like the other leading researchers in the pathology of cervical diseases who succeeded TeLinde, she possesses that rare combination of training in gynecologic pathology and gyn. An energetic, independent and curious woman, she is a translational researcher at heart. Since the day she met Pardoll, she has schooled herself on every aspect of the HPV vaccines, religiously attending lab meetings, reading journal articles and taking courses in immunology. When she was tapped as principal investigator for the clinical trials, she determined to do more than just pinpoint candidates for the vaccines. "I want to actually know what Iím doing and not just be a hunter-gatherer," she says. "That is an incredibly offensive concept to me."
To pave the way for a thoughtful selection of patients, she established a Cervix Center for women with abnormal Pap smears. Today, upwards of 400 patients annually are treated by a core staff that includes colposcopists, oncologists, pathologists and social workers. A Web site about the center for area physicians who make referrals also offers information to patients with cervical problems.
Last spring, after years of preparation, it appeared that everything was at last in place for the long-awaited human experiment. And yet, for months the trials stalled as the NIH dragged its feet in funding the lab work. Industry, which the researchers had counted on to support the trials, was less enthusiastic, in part because cervical cancer is seen as a disease of poor countries where few have the wherewithal to pay for sophisticated therapies like this vaccine. Casting a shadow over all was last yearís gene therapy death at the University of Pennsylvania, a development that subjected the project to unprecedented, stepped-up scrutiny.
Then, in midsummer, the Pardoll-Wu-Trimble ship came in. The NIH announced that it was awarding the researchers a $3.5 million Vaccine Center Grant to support the immunologic studies in the lab. It also gave a five-year junior faculty training grant to Trimble for translational research. A drug company, meanwhile, stepped up to the plate to fund preliminary vaccine trials.
By mid-July, Trimble had launched an initial, observational trial with 15 patients receiving regular treatment. By the end of the month, Hopkinsí Joint Commission on Clinical Investigation was reviewing the protocol for the full study, and the investigators were preparing to roll out their series of vaccines, one by one.
If it demonstrates nothing else, the HPV vaccine story shows the difficulties of translating research into the clinic; itís been years since Wu developed his tumor model and then worked with Pardoll to do the first successful experiments with the vaccine in mice. But the story also shows just how fast science today is galloping ahead of patient treatment. Laboratory researchers have learned to diagnose HPV with a simple molecular test, and appear to know how to treat it with a vaccine, but physicians worldwide continue to use their decades-old methods to diagnose and treat the condition.
But Pardoll believes these HPV vaccines could play a role in ushering in an immunologic revolution. One day, he says, vaccines will be a first line of defense against cancer. "Iím betting my life on it."
To learn more about Connie Trimble's work, visit the Johns Hopkins Cervical Dysplasia Web site.