The Phase I study results from research at the University of Michigan Health System presented today in New Orleans by James D. Geiger, M.D., UMHS assistant professor of surgery and the study's principal investigator, at the annual meeting of the American Association for Cancer Research.

The research suggests that dendritic cells spiked with cancer proteins from a pediatric patient's own tumor can generate an immune response to the cancer -- and may spark stabilization or regression of metastatic, or spreading, cancers.

One of the 13 study participants, a 16-year-old with cancer that had spread to her lungs and spine, showed significant tumor regression. Five others saw their disease stabilize.

"We've shown that dendritic cell vaccines seem to have the best potential of all other cancer vaccines we've looked at so far to potentially change the immune response to tumors," Geiger says. "This study is certainly not a home run, but it does give us a lot of encouragement."

Geiger calls dendritic cells the "quarterbacks" of the immune system. They 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.

In the study performed at the U-M Comprehensive Cancer Center, blood was drawn from each of 13 children, ages 3 to 17. All of the children had end-stage cancer - relapsed solid malignancies that had failed to be successfully treated with standard therapies. Among the 13 children, a variety of pediatric tumor types were treated including three neuroblastomas, four sarcomas, one osteosarcoma, one fibrosarcoma, two undifferentiated sarcomas, one renal sarcoma, and one Wilms' tumor.

From each patient's blood, the U-M team isolated dendritic cells, enticed them to replicate, then sensitized them to the tumor before injecting them back into the patient.

Earlier U-M basic research by James J. Mulé, M.D., Ph.D., professor of surgery and director of the U-M Tumor Immunotherapy Program, revealed that when dendritic cells find cancer cells, they sound the alarm to the rest of the immune system by displaying pieces of digested tumor proteins called antigens on long projections.

The dendritic cell presents these antigens to other white blood cells called T-lymphocytes until it finds those lymphocytes with receptors that fit the tumor antigen. Once a match is made, T-lymphocyte "clones", all equipped with the exact receptor needed to attack and destroy one specific type of tumor cell, attack the cancer cells.

Cancer cells can hide from lymphocytes by becoming almost invisible. Instead of displaying all their proteins on their surfaces, the cancer cells keep most of their proteins inside where the T-lymphocytes cannot find them. Dendritic cells can super-sensitize the T-lymphocytes to recognize the few proteins that remain on the cancer cell surfaces, triggering an intense immune system response.

For the 13 patients in the U-M clinical trial, tumor cells obtained from a biopsy of the patients' own tumors were ruptured by freezing and thawing, creating tumor-cell lysates. The freezing and thawing causes the antigens, which often "hide" inside of tumor cells, to be released. The lysates from each child's tumor were mixed with a protein and then added to the child's dendritic cells.

The protein/lysate mixture activates the dendritic cells, allowing them to "teach" the T-lymphocytes to recognize the antigens - and ultimately the tumor cells - in the patients' bodies. The activated dendritic cells are then injected back into the patient once every two weeks, a total of three times.

"All vaccines were delivered in an outpatient setting with no obvious toxicity," Geiger says. "Additionally, we found that it is feasible to generate large quantities of functional dendritic cells from pediatric patients, even those with a large tumor burden."

Results showed significant regression in a 16-year-old with metastatic fibrosarcoma of the lungs and spine. Five patients achieved stable disease including three that had minimal disease at the time of the vaccine therapy and their cancers did not progress for at least eight to 20 months. Some of the remaining patients did not finish therapy or succumbed to the cancer.

In the next phase of the trial, Geiger says he and his fellow researchers hope to find ways to improve the vaccine, employing methods to augment it and using it to treat patients with minimal disease who have finished more standard treatments.

"This would allow us to have a better chance to impact the health of the patients," Geiger says. "Immunotherapies are likely most effective when they are used early or when used after a standard treatment, when there's only microscopic disease present."

This work was supported by grants from the National Institutes of Health's National Cancer Institute and the University of Michigan Health System General Clinical Research Center.

Other researchers on the project were: Raymond Hutchinson, M.D., U-M professor of pediatrics and communicable diseases and clinical director of Pediatric Bone Marrow Transplantation; Lyndon Hohenkirk, M.D., research fellow, pediatric surgery; Elizabeth McKenna, M.S., research associate; Alfred Chang, M.D., professor of surgery and division chief of surgical oncology; and James Mulé, M.D., Ph.D., Maude T. Lane Professor of Surgical Immunology, director of the U-M Tumor Immunology Program.

[Contact: Valerie Gliem, Kara Gavin]

27-Mar-2001