Strengthening the immune system's fight against brain cancer

When cancer strikes, it may be possible for patients to fight back with their own defenses, using a strategy known as immunotherapy. According to a new study published in Nature, researchers have found a way to enhance the effects of this therapeutic approach in glioblastoma, a deadly type of brain cancer, and possibly improve patient outcomes.

The research was funded by the National Institute of Neurological Disorders and Stroke (NINDS) as well as the National Cancer Institute (NCI), which are part of the National Institutes of Health.

“The promise of dendritic cell-based therapy and other immunotherapies for brain cancer has been upheld for some time, but an important implication of this work is a demonstrated capacity to significantly improve the clinical impact of immunotherapy for patients with this very difficult disease,” said Duane A. Mitchell, M.D., Ph.D., director of the Brain Tumor Immunotherapy Program at the University of Florida in Gainesville and co-lead author of the study.

Dendritic cells are specialized immune cells that normally capture microorganisms, and then migrate to the lymph nodes to prepare other immune players, such as T cells, to fight off the invaders.

Dendritic cells have been used for immunotherapy to target a variety of tumor types, including those that affect the brain. These cells are taken from the patient, engineered to express antigens from the tumor¬ to create a vaccine, and then injected back into the patient. Once in the patient, the engineered dendritic cells activate T cells, which can fight the tumor and also prevent it from coming back, via an immune memory response.

Dr. Mitchell and his colleagues wanted to know if increasing dendritic cell migration to lymph nodes would improve the effects of the vaccine. To test this idea, a group of glioblastoma patients was randomized to receive a tetanus booster shot before getting the tumor-antigen expressing dendritic cell vaccine.

The booster was designed to set off an inflammatory response at the site of the vaccination, prepping the immune system for a larger battle. The other group of patients were injected with their own native dendritic cells instead of a tetanus shot, and then treated with the tumor-antigen expressing dendritic cell vaccine. Both sets of patients were treated with the vaccine which was being tested for effectiveness against glioblastoma.

The vaccine used in this study was targeted against cytomegalovirus (CMV). Studies have shown that CMV is found in glioblastoma tumors, but it is unclear if the virus causes tumors or contributes to disease progression. Glioblastomas are a devastating form of brain cancer with five year survival rates under 10 percent. From the time of diagnosis, average survival time is less than two years.

“The role of CMV in glioblastoma has been a controversial area of research for several years. These new findings, and especially the dramatic survival rates, suggest that the virus may be an effective target for immune therapy. The results presented by Dr. Mitchell and his colleagues should stimulate more basic research on CMV and its potential therapeutic role in brain tumors and possibly other cancers,” said Jane Fountain, Ph.D., program director at the NINDS.

The results showed that administering a tetanus booster before the vaccine increased dendritic cell migration to lymph nodes and also had a significant effect on clinical outcomes. The patients who received the tetanus booster lived more than 36.6 months after diagnosis compared to an average survival time of 18.5 months in those who received dendritic cells alone.

“We did not expect that enhancing dendritic cell migration would be associated with such a dramatic improvement on clinical outcomes in our patients,” said Dr. Mitchell.

Next, the investigators used a mouse model to determine how the tetanus booster increased dendritic cell migration to the lymph nodes. The results suggested that giving a booster shot to mice that have received the tetanus vaccine activated a recall response in the exposed T cells. Acting through a chemical messenger known as CCL3, those T cells increased dendritic cell migration to the lymph nodes, which ultimately enhanced the effect of the dendritic cell vaccine on tumor growth suppression.

“Dendritic cell vaccines targeting glioblastoma can be very effective by enhancing migration of dendritic cells. We now understand how we may improve outcomes for patients receiving this type of therapy,” said Dr. Mitchell. He added that larger clinical studies need to be conducted to confirm these results.

In addition, more research is necessary to define the role of CMV in glioblastoma and further determine mechanisms to enhance efficacy of vaccines in cancer therapy.

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This work was supported by grants from the NINDS (NS20023, NS067037) and the National Cancer Institute (CA108786, CA177476, CA134844).

References:

Mitchell et al. “Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients,” Nature, March 11, 2015.

The NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

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