mong the projects currently under way are new takes on monoclonal antibodies—proteins engineered to mark cancer cells for destruction by the immune system. The darlings of biotech when they debuted a few decades ago, many monoclonal antibodies have performed superbly in the lab, but scientists are often disappointed to discover that what’s true of mice isn’t necessarily true of men. Unless the antibodies are at least partially humanized into what’s known as a “chimeric” form, the immune system will attack the antibodies as invaders, rather than welcoming them as reinforcements.

Thanks to countless hours of painstaking work by University of Miami clinicians, researchers, and physician-scientists such as Eckhard Podack, M.D., Ph.D.—UM/Sylvester’s associate director for basic science and chair of the University’s Department of Microbiology and Immunology—a handful of the dozens of monoclonal antibodies developed in the past several years are progressing toward therapeutic status. One of these is SGN30. First developed by Podack in 1992, SGN30 labels a protein on the surface of Hodgkin’s and other lymphoma cells with the biochemical equivalent of a bull’s eye, making them easy pickings for the immune system’s killer T cells.

“All the work in oncology these days is going toward more targeted therapies like this one,” says UMhematologist/oncologist Hugo Fernandez, B.S. ’85, M.D., a participating investigator in a multicenter Phase II trial of SGN30. “We can’t say it’s a cure, but SGN30 does show some promise to be a helpful, less-toxic alternative to chemotherapy for certain lymphomas.”

Podack has also developed a compelling contender in another immunotherapy category—genetically engineered whole-cell vaccines. Developed for people with lung cancer (which claims more lives than any other type of cancer), the B7 vaccine is an endeavor even more audacious than at first it sounds.

“Hardly anyone works on cancer vaccines for lung cancer because lung cancer is non-immunogenic—the immune system is completely blind to it,” says Podack. “But that’s precisely why I think it’s the right malignancy to target with a vaccine: A lung tumor has never seen an immune response and has no defenses against it.” To mount the attack, Podack genetically modifies lung cancer cells to express the B7 ligand, a protein that activates T cells in the immune system and directs them to the tumor.

“We tested B7 in 19 people who were considered terminally ill with non-small-cell lung cancer,” says Luis Raez, M.D., co-leader of the UM/Sylvester Lung Cancer Site Disease Group. “Today, six of them are disease-free, and three have passed three years with no sign of relapse.”

Marilyn Cohn, a 66-year-old Boynton Beach woman who was given one year to live nearly four years ago, is one of those three-year survivors. “I feel very blessed,’’ she says. “The vaccine has given me more time to spend with my grandchildren.” An upcoming, more extensive trial will involve 48 patients after surgery or their first course of chemotherapy.

Research associate professor Seung-Uon Shin and Rosenblatt are working on a novel strategy involving suppression of B cells to stimulate cancer-fighting T cells. “We noticed that tumors don’t grow as well in mice that are deficient in B cells as in normal mice,” says Shin. “We have known for years how to safely deplete B cells in humans, so we are investigating in mice whether using a monoclonal antibody called rituximab against the B cells will improve T-cell immune response to cancers. If so, this could readily be applied to humans.”

Anti-angiogenesis—which seeks to prevent or reverse the development of blood vessels that nourish tumors—is receiving considerable attention. Shin just received a major Department of Defense grant to work on a fusion protein that combines an antitumor antibody with an anti-angiogenic protein known as an endostatin. The antibody enables endostatin to concentrate at the tumor site. “The blood vessels of treated tumors are thinner and have fewer branches, which leads to marked slowing of tumor growth,” Shin says.

A discovery from the lab of Diana Lopez, M.S. ’68, Ph.D. ’70, also is causing excitement. Seeking a tumor marker to look at immune responses in cells a few years ago, Lopez and her team discovered that the tumors in their animal models stopped growing. Exhaustive sleuthing traced the protective effect to a unique amino acid peptide dubbed IEG-1. The peptide has been licensed for development by Viragen.

“It’s very exciting that this discovery might actually do someone some good,” says Lopez, for whom the experience epitomizes the frustrations and joys of lab life. “Often when I’m looking for something, I find I have nothing; then I get something I wasn’t expecting.”

In addition to serendipitous discoveries, the quest for cancer cures creates strange bedfellows, as scientists seek to turn foes such as viruses into friends. “People have noticed for centuries that the tumors of people with cancer often stopped growing when they contracted a viral infection,” says Glen Barber, professor of microbiology and immunology. “The reason is that viruses replicate very well in nearly all cancer cells, which seem to lack antiviral machinery.” Barber’s current work employs a virus known as vesicular stomatitis, or VSV, which replicates rapidly inside tumor cells until they burst. “It replicates so fast that one turns into 10,000 in just eight hours,” Barber says. Yet VSV has virtually no effects on either mice or humans.

UM oncologist Khaled Tolba, M.D., is exploring the viral vector approach with a more virulent organism: herpes simplex virus (HSV), which causes cold sores. Currently focusing his efforts on chronic lymphocytic leukemia, a slow-growing malignancy that affects older adults, Tolba believes his work offers potential against other leukemias as well. “The number of tumor cells in the body is 10 to the 10th or 11th power,” Tolba says. “We plan to take less than one-thousandth of those cells, introduce a modified form of HSV into them, and put them back. What we do has to be powerful enough to make the immune system attack not only those cells, but the 99.9 percent that we didn’t touch.”

Tolba, Shin, and Barber are all hoping to take their therapies to Phase I trials in the future. Of course, when a possible new weapon in the cancer arsenal finally makes it to clinical trials, new challenges loom. It is an intricate, expensive process that requires hundreds of hours of specialized surveillance.

For all the difficulties, however, the University’s cancer researchers truly love what they do. “Our research is animated by people’s need for new treatments,” says Rosenblatt. “You have to derive enormous satisfaction from a good lab result. True scientists enjoy the twists and turns along the way.”