Radiation and intratumoral injection turn on immune system to attack brain tumor cells

Researchers at Cedars-Sinai’s Maxine Dunitz Neurosurgical Institute are working to develop a non-surgical approach to brain cancer that uses radiation and the injection of specially cultured bone marrow cells into the tumor. The combination sets in motion a local and systemic immune response to kill surviving tumor cells.

The novel approach has provided promising results in a study on rats, described in the March 3 issue of the Journal of Immunotherapy. Human trials are expected to begin within the year, according to John S. Yu, M.D., senior author of the article and co-director of the Comprehensive Brain Tumor Program at the Institute.

This therapy may prove to be an important step in the development of dendritic cell immunotherapy, which Institute neurosurgeons and scientists have been using experimentally for the past few years. Early results have shown promise for extending length of survival in patients with highly aggressive brain tumors called gliomas.

Dendritic cells, elements of the immune system, “clean up” foreign proteins and in the process identify them as invaders for the immune system’s T-cells to attack. This is a key role because several mechanisms allow glioma cells to grow and spread without being detected by the immune system.

In current dendritic cell immunotherapy, neurosurgeons must first surgically remove tumor cells from the patient’s brain and culture them with dendritic cells in the laboratory. When the resulting “vaccine” is injected under the skin, the dendritic cells recognize tumor cells as invaders, triggering an immune response. The new approach is based on recent studies showing that dendritic cells can identify dying tumor cells in the body, not just tumor cells they are exposed to in the laboratory.

“If the good results we’ve seen in the animal study are repeated when we move into human trials, we may be able offer hope even for patients who have brain tumors in locations that cannot be accessed surgically,” said Keith L. Black, M.D., one of the article’s authors and director of the Maxine Dunitz Neurosurgical Institute. “Over the course of the past several years, we have been involved in a number of research findings that we think will lead to dramatic changes in the way these deadly tumors are treated. Instead of exposing the patient to harsh therapies that bring with them side effects and serious risks, we’re moving toward helping the immune system heal the body itself.”

A pioneer in the use of dendritic cell immunotherapy to combat brain tumors, Dr. Black directs the medical center’s Division of Neurosurgery and the Comprehensive Brain Tumor Program, and he holds the Ruth and Lawrence Harvey Chair in Neuroscience.

In the animal study, dendritic cells taken from bone marrow and cultured were injected into gliomas that contained some tumor cells that had been exposed to radiation and others that had not. As the dendritic cells began taking up and processing pieces of dying tumor, they set off a local immune system response, enlisting T-cells to destroy the tumor.

Injected dendritic cells also moved into regional lymph nodes where they would be able to activate additional T-cells to fight metastatic cancer cells. Migration to the lymph nodes also initiated a systemic immune response, enlisting other “cytokines” against glioma cells. Furthermore, dendritic cells are associated with the secretion of Interleukin-12, a naturally occurring chemical that Institute researchers have found to be extremely effective in killing glioma cells.

This is the first study in which dendritic cells have been delivered directly into brain tumors with therapeutic success. Animals receiving the dendritic cell treatment lived considerably longer than controls. Even after having new tumors implanted later, rats that had been treated with dendritic cell immunotherapy continued to survive, an indication of the long-lasting benefits of the vaccine.

Researchers hope similar benefits – with improved success rates and less need for open surgery – will be seen when the therapy moves into human trials. Radiosurgery – which focuses radiation beams from hundreds of computer-selected angles on a tumor – kills cancer cells while minimizing damage to nearby tissues and vital structures. Rarely, however, is a tumor completely obliterated. The initiation of immunotherapy is intended to “mop up” the tumor cells that escape.

Moneeb Ehtesham, M.D., post-doctoral fellow at the Institute, is the article’s first author. The work was supported in part by grant NS02232 to Dr. Yu from the National Institutes of Health.

Cedars-Sinai Medical Center is one of the largest nonprofit academic medical centers in the Western United States. For the fifth straight two-year period, it has been named Southern California’s gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 “Most Wired” hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.