ANN ARBOR, Mich.---Interleukin-2, a well-known weapon in the fight against cancer, has proven to be a powerful new addition to a University of Michigan cancer vaccine that mobilizes the body's own immune system to attack and destroy malignant cells.
In a study published in the March 2 issue of the Proceedings of the National Academy of Sciences, U-M researchers present the results of experiments testing the effectiveness of the vaccine/IL-2 combination on laboratory mice with large, advanced sarcomas or breast cancers. While not included in the PNAS article, U-M scientists also are studying other types of tumors, including aggressive skin cancers called melanomas, to determine their response to the vaccine/IL-2 combination.
It is the first study to combine interleukin-2, a growth factor that stimulates immune system cells to divide and multiply, with a cancer vaccine made from specialized white blood cells called dendritic cells, which alert the body's immune system to the presence of cancer.
"The addition of IL-2 substantially improved our vaccine's anti-tumor effect," said James J. Mulé, Ph.D., professor of surgery in the U-M Medical School, director of the Tumor Immunotherapy Program in the U-M Health System's Comprehensive Cancer Center and a member of the U-M Life Sciences Commission.
"Some mice with well-established, advanced lung and skin tumors showed no evidence of disease after treatment," Mulé said. "Others experienced substantial tumor regression and lived longer than mice treated with either the vaccine or IL-2 alone."
Based on these results, U-M researchers have requested approval to begin a Phase II trial of the cancer vaccine with IL-2 in adults with advanced metastatic melanoma.
Dendritic cells alert the immune system to cancer by presenting pieces of digested tumor proteins called antigens to white blood cells called T-lymphocytes. When the dendritic cell finds a T-lymphocyte with a docking site to match the tumor antigen, the T-cell starts producing messenger chemicals which stimulate production of T-lymphocyte "clones." All these new T-cells are equipped with the exact receptor needed to immobilize and destroy one type of cancer.
While the U-M's dendritic cell vaccine alone triggered an immune response against cancer cells, it could not produce antigen-activated T-lymphocytes fast enough to overcome large, well-established tumors, according to Mulé.
"IL-2 gives the immune response a boost," Mulé said. "First, dendritic cells find and activate T-cells with the specific receptors we need to fight the tumor. Then IL-2 induces those T-cells to rapidly divide and proliferate."
The fact that interleukin-2 works at low doses in combination with the U-M cancer vaccine is important, Mulé added, because the toxic effects of high-dose IL-2 therapy have limited its effectiveness against cancer in the past.
"Dosages of IL-2 used in our study were 25 to 50 times lower than the maximum tolerated dosage," Mulé said. "They were comparable to the low dosages used today to stimulate immune response in people with HIV or patients undergoing bone marrow transplantation."
Significant results from the U-M study include:
¤ Mice injected with three times the lethal dose of tumor (sarcoma) cells and then vaccinated with a sarcoma-specific dendritic cell vaccine showed substantial reduction in tumor size, while mice receiving the same vaccine with IL-2 remained disease free.
¤ Eighty percent of mice with well-established sarcomas showed complete regression of their tumors after being treated with the U-M vaccine and IL-2.
¤ Sixty percent of mice whose original sarcomas and breast cancers had spread in their lungs showed no evidence of disease after treatment with the dendritic cell vaccine in combination with interleukin-2. The other 40 percent of mice treated with the vaccine/IL-2 combination had fewer than 10 nodules compared to greater than 250 nodules in control mice.
¤ Mice with well-established secondary lung tumors receiving vaccine in combination with IL-2 lived more than twice as long as mice receiving vaccine or IL-2 alone.
¤ Even mice with large, late-stage sarcomas showed regression in tumor size after combination treatment and lived significantly longer than mice receiving either the vaccine or IL-2 alone.
While other researchers are experimenting with tumor vaccines made from single tumor peptides mixed with dendritic cells, Mulé and his colleagues 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, making it less likely that tumor cells will escape detection," he said.
In addition to Mulé, co-authors on the PNAS study are Koichi Shimizu, M.D., U-M research fellow; Ryan C. Fields, who received his U-M undergraduate degree in 1998 and is now attending Duke University Medical School; and Martin Giedlin, associate research director for vaccines and gene therapy research at Chiron Technologies.
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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