Neuroblastoma is a cancer that arises in immature nerve cells and affects mostly infants and children. The disease often has already spread throughout the body by the time the disease is diagnosed.
The St. Jude strategy represents the successful translation of concepts into a combination therapy that proved effective in laboratory models of neuroblastoma; and that now includes the production of the drugs made to the high standards required for human clinical trials, the researchers say.
Translating this kind of research into the clinic is important because today only 40 percent of children with neuroblastoma can be cured; children who suffer relapses following treatment are virtually incurable. The St. Jude study suggests that the immune system can be manipulated to target cancer cells that have become resistant to traditional chemotherapy.
"This is an extraordinary model for advancing the field of pediatric oncology," said Raymond Barfield, M.D., Ph.D., an assistant member of Hematology-Oncology at St. Jude. "We were able to make rapid progress by doing all the development and production of the antibody on campus. Now we're planning to submit a proposal to the Food and Drug Administration to begin a Phase I trial of this strategy that will permit us to begin exploring ways to use this antibody technique to treat children with neuroblastoma."
The investigational therapy comprises artificial antibodies that tag neuroblastoma cells, immune system cells such as T lymphocytes that attack those tagged cells, and proteins called cytokines that stimulate the T lymphocytes. A report on these preclinical studies appears in the December 1 issue of Clinical Cancer Research.
The St. Jude strategy represents an improvement on a similar technique that showed great promise during clinical trials in Germany and elsewhere, according to Barfield, who is a co-author of the Clinical Cancer Research paper. Prior antibodies caused troublesome side effects, such as fever and pain, which restricted the level of antibody that could be used in the treatment, Barfield said. "However, the antibody we used in our laboratory study appears to be less likely to cause side effects," he said. "That suggests that it could be used in humans at higher levels that may improve the effect of the antibody."
The St. Jude team showed that their treatment could trigger a sustained, highly targeted immune system attack on disseminated (spread over a large area) cancer cells in laboratory models. Moreover, the treatment can be readily transferred to the clinic because each of the three parts of the treatment can be produced at St. Jude at a quality suitable for use in humans, the researchers said.
"Our success with this therapy is especially important because neuroblastoma rapidly spreads through the body, making it difficult to treat," said Mario Otto, M.D., Ph.D., a postdoctoral research fellow at St. Jude. "And many children who are successfully treated suffer a relapse within five years because of the presence of small populations of cancer cells that survive the initial treatment. The question is how to get rid of those few cells that have escaped chemotherapy and can cause relapse. One promising answer is immune therapy that specifically targets these remaining cells." Otto is first author of the paper.
The St. Jude researchers infused into a laboratory model of neuroblastoma an antibody called hu14.18, which sought out and bound to a protein called GD2 on the surface of neuroblastoma cells. They also infused a special type of T lymphocytes called gamma-delta T cells, which attacked the cancer cells that were tagged by hu14.18. In order to stimulate the growth and activity of the gamma-delta cells, the researchers infused an artificial protein called Fc-IL7. IL-7 is a cytokine--a protein that promotes T-lymphocyte survival and proliferation. The Fc protein (immunoglobulin) that is fused to IL-7 slows the process by which the body disposes of this cytokine. The researchers isolated the gamma-delta-T lymphocytes from blood samples obtained from healthy human volunteers.
While the hu14.18 antibody does not directly kill neuroblastoma cells, it does trigger so-called antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is an arm of the immune system that destroys cells using immune system cells such as "natural killer" cells, and other immune cells, such as such as the gamma-delta-T cells that are part of the St. Jude combination treatment.
"The hu14.18 greatly increased the ability of the gamma-delta-T lymphocytes to trigger ADCC," Otto said. "This antibody was key to the success of our strategy."
The other authors of this paper include William J. Martin, Rekha Iyengar, Wing Leung, Thasia Leimig and Stanley Chaleff (St. Jude); Stephen D. Gillies (EMD Lexigen Research Center, Billerica, Mass.), and Rupert Handgretinger (St. Jude; currently at University of Tübingen, Germany).
This work was supported in part by a Cancer Center Support Grant, ALSAC and the Assisi Foundation of Memphis. The antibody and the fusion protein Fc-IL7 used in the present study were provided by EMD Lexigen (Billerica, Mass.).
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.