ANN ARBOR---Using a vaccine made from specialized white blood cells called dendritic cells spiked with cancer proteins, University of Michigan scientists have found a way to activate the immune system to attack malignant tumors and prevent the development of new tumors in mice.
"Immunization with the dendritic cell vaccine was effective against two types of solid tumors---sarcomas and breast carcinomas---in two unrelated strains of mice," said James J. Mulé, professor of surgery in the U-M Medical School and director of the Tumor Immunotherapy Program in the U-M Health System's Comprehensive Cancer Center. "Based on these encouraging results, we have begun a Phase I clinical trial in pediatric and adult patients with advanced solid tumors."
Results of the study were published in the Aug. 4 issue of the Proceedings of the National Academy of Sciences. Ryan C. Fields, from Bloomfield Hills, Mich., who received his U-M undergraduate degree in May 1998, and Koichi Shimizu, M.D., U-M research fellow, are joint first authors on the study.
Fields, Shimizu and Mulé used immature dendritic cells from mouse bone marrow as the basis for their vaccine. Dendritic cells are specialized white blood cells whose job it is to alert the immune system to the presence of invading cancers, bacteria or viruses, so the invaders can be surrounded and destroyed. When they find cancer cells, dendritic cells sound the alert by displaying pieces of tumor proteins called antigens on long projections extending from the center of the dendritic cell.
Like Cinderella's prince searching for a woman who matches the glass slipper, the dendritic cell presents these antigens to other white blood cells called T-lymphocytes until it finds those with receptors that fit the tumor antigen. Once a match is made, T-lymphocytes produce messenger chemicals which stimulate production of a flood of T-lymphocyte "clones," all equipped with the exact receptor needed to attack and destroy one specific type of tumor cell.
"Cancer cells often hide from lymphocytes by becoming invisible," Fields explained. "Instead of displaying foreign proteins on the surface of tumor cells, most remain inside the cell where the immune system cannot detect them. Dendritic cells bring these hidden antigens out of hiding triggering this intense immune system response."
While other researchers are experimenting with tumor vaccines made from single tumor peptides mixed with dendritic cells, Mulé and his colleagues were the first to use whole tumors called lysates---tumor cells which have been frozen and thawed several times to kill them. "By using the entire tumor cell, we are sensitizing the immune system to attack all the antigens in that tumor, rather than just one or two," said Mulé. "A broader immune response makes it less likely that tumor cells will escape detection."
Significant results from the U-M study include:
¤ When Fields and Shimizu mixed mouse dendritic cells fed with sarcoma tumor lysates with T-lymphocytes in a test tube, they generated a flood of new T-lymphocytes primed to kill the sarcoma. When live sarcoma cells were added to the mixture, T-lymphocytes killed 70 percent of the sarcoma cells within four hours.
¤ Mice vaccinated with the sarcoma-specific dendritic cell vaccine and then given a lethal dose of live sarcoma cells remained tumor free for at least 100 days.
¤ Mice with secondary tumors in their lungs had a 90 percent reduction in lung metastases after dendritic cell vaccination.
¤ When CD8 T-lymphocytes were removed from the immunized animal, the dendritic cell vaccine lost its therapeutic effect. When CD4 T-lymphocytes were removed, the effect was greatly diminished.
U-M scientists use immature dendritic cells fresh from the bone marrow's production factory, rather than mature dendritic cells which have already circulated through the lymphatic system to other organs. "At this early undifferentiated stage of development, it is easier to sensitize them to react to an individual's specific cancer antigens," Mulé explained.
The research was supported by the National Cancer Institute/National Institutes of Health, the U.S. Army Research Office and by gifts from C.J. and E.C. Aschauer and Abbott Laboratories to the U-M's Department of Surgery and the Tumor Immunotherapy Program.
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