Vitetta began her scientific career at New York University School of Medicine and graduate school. "The first time that I met Ellen was in 1966, when I gave an immunology lecture in the medical microbiology course. After the lecture, a young student came up to me and asked how B cells switch from producing IgM antibody to IgG antibody and why this switch was necessary. I told her I did not know. Even then, I sensed a spark and an intelligence about her that was unusual for such a young student. Ironically, some two decades later, Ellen and her group first described the cytokine, IL-4, that induces the switch from IgM to IgG," recalls Jonathan Uhr, today a professor in the Cancer Immunobiology Center at the University of Texas (UT) Southwestern Medical Center in Dallas, where Vitetta is the director and holder of the Scheryle Simmons Patigian Distinguished Chair in cancer immunobiology.
Vitetta's move westward coincided with a turning point in immunology-the invention by George Kohler and Cesar Milstein of monoclonal antibody technology. "When I read their paper in 1975, a light bulb went off and I knew that targeted therapy using monoclonal antibodies was the way to go after many diseases, including cancer. In 1986 I took a research leave and worked at the Medical Research Council in Cambridge, England, headed by Milstein, to learn molecular engineering of antibodies and immunotoxins," she recalls.
And the rest, as they say, is history. In 1994 she became president of the American Association of Immunologists and was elected to the National Academy of Sciences.
At the Friend lecture in April, Vitetta took listeners on her "20-year voyage" to attach a portion of the castor bean toxin ricin to a monoclonal antibody that seeks out and destroys lymphoma cells. "When it worked in mice, we thought that we were home free," Vitetta recalled. But in humans, liver toxicity occurred. Philip Thorpe, professor of pharmacology at UT Southwestern, led the effort to tame the toxicity, which stemmed from the immunotoxin's binding to mannose receptors on liver cells. Removing the mannose from the toxin, the researchers solved that problem, and a second generation of immunotoxins was born, with promising results in a mouse model of human lymphoma that Maria-Ana Ghetie, assistant professor at the center, developed. Next, Victor Ghetie, a professor in the center, led the scale-up of production and expanded animal testing. Clinical trials begun in the late 1980s yielded impressive 15% to 40% response rates, but with a nasty side effect: vascular leak syndrome (VLS). "The blood vessels leak fluid into tissues, causing edema and, at very high doses, life-threatening organ failure. This doesn't occur in mice, rabbits, rats, or monkeys," said Vitetta.
The researchers went back to the lab to identify the part of the toxin that damages vascular endothelial cells. Using monolayers of human umbilical vein endothelium and mice with human foreskin on their backs, postdoctoral researcher Roxana Baluna identified three linked amino acids in ricin that cause VLS. But deleting the tripeptide didn't work-it either dampened the needed toxicity, or the VLS remained. Finally, postdoctoral researcher Joan Smallshaw tweaked a nearby amino acid and obtained the desired effect: the mutated recombinant toxin did not induce vascular leak in their models. But will it work in humans? "Right now I am writing three grants to raise funds for the clinical trial," says Vitetta.
And that going-the-next-step is what distinguishes Vitetta's research. "Having practiced basic science for the first half of her career, she decided to change to translational research using antibody-based therapies to treat patients with cancer. She insisted on building a Food and Drug Administration-approved scale-up laboratory in the medical school to make her own drugs. Vitetta is one of a very few basic scientists who have brought their discoveries to the clinic," says Uhr. But it hasn't been easy. "If you have only done basic research, you think that translational research is 'second-rate science.' Life and rewards at medical schools are all about hot discovery papers and cutting-edge technology-not about slogging through the mud to get a discovery to work in humans. In addition one has to learn 10 new skills both within and outside science. But, I am convinced that it is critical that translational science be done in academia and with the same high-quality standards that we require of basic research. Despite its lack of popularity, that is what I try to do," Vitetta says.
Vitetta is both research powerhouse and untiring activist. Relates Uhr, "Watching her in action is exhausting. Besides science, she is very devoted to her school, women's issues, and teaching. As a teacher, she is outstanding-clear, funny, and able to make complex issues understandable to everyone. She has won many teaching awards from the medical students. Her presentations at meetings are always remembered."
That will certainly be the case for the fifth annual Charlotte Friend Memorial Lecture.