Researchers at the University of Pennsylvania Medical Center have devised aunique and rapid way to transform plentiful monocytes into battle-readydendritic cells in an effort to boost the immune system's cancer-fightingforces. In test-tube cultures, the modified cells have already shown theirability to activate T cells within one week.
Penn investigators collaborated with a team from the National CancerInstitute in this ongoing research. The next step, the scientists say, will beto demonstrate that the dendritic cells can induce a clinically useful and saferesponse 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 vaccinesare typically thought of as a preventative treatment--administered to patientsbefore contracting a disease--most cancer vaccines are designed to spur theimmune system into attacking existing tumors. Czerniecki and colleagues reporttheir 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 surfacesto attract the attention of T cells. The dendritic cells and their antigen flagstravel to the lymph nodes--where T cells reside--and display the antigens toactivate T cells. The T cells then trigger a complicated immune response toeliminate the antigens, including those on tumor cells.
Until recently cancer vaccines have used additives called adjuvants tomobilize dendritic cells. Now, scientists have found ways to generate dendriticcells 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 enoughdendritic cells, which make up only 1 percent of the peripheral blood. Tocompensate for such a minuscule pool, Czerniecki's team looked to monocytes astheir starting cell type because they account for 10 percent of human blood.
This hypothesis--described by Cerzniecki and his NCI collaborator PeterCohen--proved golden because the researchers' method not only yielded dendriticcells from monocytes, but created them in surprisingly large quantities, andwith amazing speed and potency. "With this technique we can supply very largenumbers of activated dendritic cells, all directed at cancer antigens," saysCzerniecki.
The scientists separate the monocytes from a donor's blood and treatthem with calcium, and now, in an as-yet unpublished step, they also addinflammatory molecules called cytokines to further activate the dendritic cells.The surface of these modified cells are tagged with a melanoma antigen. Theflagged dendritic cells are then grown with the donor's T cells, and after oneweek, even T cells from donors without melanoma can fight melanoma tumors.
Using the modified dendritic cells, the team of Czerniecki and Cohenplans to conduct a human clinical trial with melanoma patients next spring. "Weplan to kick start the immune system of these patients by giving themmelanoma-antigen-labeled dendritic cells," he explains. "These cells will havethe instructions to activate T cells to find the melanoma tumor and work atshrinking it." Using a similar, but weaker vaccine, German colleagues ofCzerniecki's have detected shrinkage and disappearance of melanoma tumors in ahandful of patients.
National Institutes of Health researchers Charles Carter and Steven A.Rosenberg also collaborated on the study, which was supported by the AmericanCancer Society, and the Arthur Pardee, Thomas B. McCabe, and HarringtonFoundations.
Materials provided by University of Pennsylvania Medical Center. Note: Content may be edited for style and length.
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