July 19, 1999 Findings take important first step toward vaccines for cancer, viruses
A single injection of specialized immune system cells -- removed from the bloodstream and exposed to a foreign substance -- can trigger a potent immune response in humans that lasts for months, Rockefeller University researchers report. The experiment provides the first conclusive evidence that one dose of these cells, called dendritic cells, can prompt a strong immune response, and it suggests new ways of improving vaccines and protecting against cancer.
"We've shown for the first time that a single injection of mature dendritic cells can induce a significant level of immunity in people," says Rockefeller's Nina Bhardwaj, M.D., Ph.D., associate professor for clinical investigation and senior author of the study. "The results indicate that this method could be a powerful new way to fight cancers and chronic infections like HIV." Bhardwaj, along with lead author Madhav Dhodapkar, M.D., a Rockefeller clinical scholar and assistant professor, and nine other colleagues reported the results of the experiment in the July 15 issue of the Journal of Clinical Investigation.
Ralph Steinman, M.D., another co-author and head of Rockefeller's Laboratory of Immunology and Cellular Physiology, which gave birth to much research on dendritic cells, says the new technique will probably first be used to treat people with advanced cancers and those who have gotten rid of the disease but are vulnerable to a recurrence. The other main targets will be chronic viral infections such as HIV, hepatitis, Epstein-Barr virus and herpes.
Dendritic cells have become the subject of increased interest by immunologists. Located in most tissues, dendritic cells are responsible for signaling the presence of an intruder to the body's T cells, which play the primary role in the immune response against invading microbes. Dendritic cells capture antigens from the foreign substance and present them to the T cells, which then know what to seek out and destroy -- and also what to leave alone.
In 1994, Bhardwaj and colleagues found they could take dendritic cells from healthy patients who had previously been exposed to a virus, infect the cells with that virus and induce the desired reaction from cytolytic killer T cells in culture. This was important because prior studies had suggested that growth factors and other types of cells needed to be present to spur the cytolytic T cells into action.
Last year, these investigators found that dendritic cells could "eat" virus-infected cells and induce killer cells directed toward viral antigens. Follow-up studies by Rockefeller Associate Professor Robert Darnell, M.D., Ph.D., and then-graduate student Mathew Albert, Ph.D., showed that dendritic cells also could acquire cancer cells and stimulate killer cells in culture from the blood cells of cancer patients.
In the latest experiment, the researchers wanted to establish some clear-cut evidence regarding the benefits of dendritic cells. They decided to study the effect in healthy, uninfected subjects rather than those with viruses or tumors because they wanted to measure the effectiveness of the cells without confounding factors skewing the results. Previous studies by other researchers in cancer patients had suggested some clinical benefit -- but those experiments used immature dendritic cells in multiple doses, sometimes with fetal calf serum, and sometimes the patients received soluble doses of antigen as well. This made it hard to be certain an immune response was directly due to dendritic cells.
The Rockefeller team made use of a set of very sensitive assays that could measure different aspects of an immune response. In addition, they used mature dendritic cells, which are more effective at stimulating T cells in culture. Earlier experiments by other researchers used immature dendritic cells, which capture antigens better but don't prompt the same level of response from T cells.
For the study, the researchers drew blood from healthy volunteers, grew a large batch of dendritic cells from the samples, and injected them back into the patients without exposing the cells to anything. (This was done for control purposes). They then measured the subjects' immune response at two different intervals and recorded no discernible change.
Several weeks later, the researchers administered a second round of injections. Some subjects received dendritic cells that had been exposed to three different kinds of antigen -- one associated with tetanus, one from influenza and one derived from a mollusc that humans would never have naturally encountered. Other subjects received the antigens alone. Once again, the immune responses of all subjects were measured after seven and 30 days had elapsed.
The researchers found that those who received antigen alone showed no change, but those receiving dendritic cells that had been exposed to the antigens demonstrated a significant immune response. The reaction to the influenza antigen was especially strong, as it was still evident four months later.
The researchers say the study's results are encouraging because it gives solid proof of the dendritic cells' effectiveness and establishes a reliable methodology for exploring the therapeutic potential of these cells. Dhodapkar is investigating ways to make the treatment more powerful by giving booster shots, varying routes of injection and looking at different maturation states of the cells that are used. He and Bhardwaj also have initiated studies at The Rockefeller University Hospital to test this approach in patients with melanoma.
"For all we know, we could be at the 10 percent level of efficiency," Bhardwaj says. "We may find increased immunity with more frequent injections or by putting more cells into each injection."
Dendritic cells were discovered in 1973 by Steinman and the late Zanvil Cohn, but the cells' central role in the immune system was not truly appreciated by other immunologists until early in this decade, largely through work conducted in Steinman's laboratory. It had been difficult to conduct experiments with the cells because their number is very small, but Bhardwaj, Steinman and colleagues in Germany developed a method to generate large numbers of dendritic cells in culture.
In addition to Bhardwaj, Steinman and Dhodapkar, the co-authors of the paper are Mark Sapp, M.D., of the New York University School of Medicine; Hema Desai, B.S., and Joseph Krasovsky, M.S., at RU's Laboratory of Immunology and Cellular Physiology; Coraleen Fossella, A.N.P., of RU's General Clinical Research Center; Sean M. Donahoe, B.S., and Douglas F. Nixon, M.D., Ph.D., of the Aaron Diamond AIDS Research Center; and P. Rod Dunbar, M.D., Ph.D., and Vincenzo Cerundolo, M.D., of the Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, United Kingdom.
The research was supported in part by a Clinical Research Career Development Award from the American Society of Clinical Oncology, by grants from the National Institutes of Health and by the SLE Foundation.
Melanoma and HIV patients who are interested in participating in ongoing studies with dendritic cells should contact Dhodapkar at 212-327-7597.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates. Thirty-three faculty members are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D.
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