Oct. 10, 1997 Researchers at the University of Pennsylvania Medical Center have devised a unique and rapid way to transform plentiful monocytes into battle-ready dendritic cells in an effort to boost the immune system's cancer-fighting forces. In test-tube cultures, the modified cells have already shown their ability to activate T cells within one week.
Penn investigators collaborated with a team from the National Cancer Institute in this ongoing research. The next step, the scientists say, will be to demonstrate that the dendritic cells can induce a clinically useful and safe response in the bodies of cancer patients.
"Our procedure could be used to produce vaccines against cancers, including breast, colon, and melanoma," says Brian J. Czerniecki, MD, PhD, assistant professor of surgery in Penn's School of Medicine. Although vaccines are typically thought of as a preventative treatment--administered to patients before contracting a disease--most cancer vaccines are designed to spur the immune system into attacking existing tumors. Czerniecki and colleagues report their findings in the October 15 issue of the Journal of Immunology.
Dendritic cells play a leading role in generating an immune response. After ingesting antigens (molecular tags, of sorts, found on all substances), dendritic cells attach pieces of internalized antigens to their outer surfaces to attract the attention of T cells. The dendritic cells and their antigen flags travel to the lymph nodes--where T cells reside--and display the antigens to activate T cells. The T cells then trigger a complicated immune response to eliminate the antigens, including those on tumor cells.
Until recently cancer vaccines have used additives called adjuvants to mobilize dendritic cells. Now, scientists have found ways to generate dendritic cells directly.
This concept is working in animal models, but the problem in humans, says Czerniecki, is that there hasn't been an easy way to produce enough dendritic cells, which make up only 1 percent of the peripheral blood. To compensate for such a minuscule pool, Czerniecki's team looked to monocytes as their starting cell type because they account for 10 percent of human blood.
This hypothesis--described by Cerzniecki and his NCI collaborator Peter Cohen--proved golden because the researchers' method not only yielded dendritic cells from monocytes, but created them in surprisingly large quantities, and with amazing speed and potency. "With this technique we can supply very large numbers of activated dendritic cells, all directed at cancer antigens," says Czerniecki.
The scientists separate the monocytes from a donor's blood and treat them with calcium, and now, in an as-yet unpublished step, they also add inflammatory molecules called cytokines to further activate the dendritic cells. The surface of these modified cells are tagged with a melanoma antigen. The flagged dendritic cells are then grown with the donor's T cells, and after one week, even T cells from donors without melanoma can fight melanoma tumors.
Using the modified dendritic cells, the team of Czerniecki and Cohen plans to conduct a human clinical trial with melanoma patients next spring. "We plan to kick start the immune system of these patients by giving them melanoma-antigen-labeled dendritic cells," he explains. "These cells will have the instructions to activate T cells to find the melanoma tumor and work at shrinking it." Using a similar, but weaker vaccine, German colleagues of Czerniecki's have detected shrinkage and disappearance of melanoma tumors in a handful of patients.
National Institutes of Health researchers Charles Carter and Steven A. Rosenberg also collaborated on the study, which was supported by the American Cancer Society, and the Arthur Pardee, Thomas B. McCabe, and Harrington Foundations.
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