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Boosting Immunotherapy Against Brain Cancer

An artist's representation of the surface of a human dendritic cell.NCI

Dendritic cells have recently been used for immunotherapy to target a variety of tumor types. Dendritic cells are isolated from the patient’s blood, engineered to express antigens from the tumor, and then injected back into the patient as a vaccine. Once in the patient, the engineered dendritic cells migrate to the lymph node and activate T cells to fight the tumor and create an immune memory to prevent the cancer from coming back.

Researchers led by Drs. Duane A. Mitchell and John H. Sampson at Duke University Medical Center tested whether a strategy to increase dendritic cell migration to lymph nodes would improve the effects of a dendritic cell vaccine against glioblastoma multiforme, the most common form of malignant brain cancer in adults. The vaccine targeted an antigen from cytomegalovirus. The role of this virus in disease progression is unclear, but past studies have found that cytomegalovirus proteins are specifically expressed in glioblastoma tumors but not in normal brain cells.

Twelve patients newly diagnosed with glioblastoma were given standard radiation and chemotherapy, and randomly divided into 2 groups. One group received a tetanus booster shot, designed to set off an inflammatory response at the site of the vaccination and prep the immune system. The other patients were injected with their own unaltered dendritic cells instead of a tetanus shot. All were then treated with the dendritic cell vaccine against the cytomegaloviral antigen. The research was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI).

The results, published on March 19, 2015, in Nature, showed that administering a tetanus booster before the vaccine increased dendritic cell migration to lymph nodes and significantly improved both the time without disease progression and overall survival. Patients who received the tetanus booster lived an average of more than 3 years after diagnosis compared to 1.5 years in those who received dendritic cells alone.

The team used a mouse model to determine how the tetanus booster increased dendritic cell migration to lymph nodes. They found that migration depended on memory T cells specific to the tetanus toxoid. Migration also depended on 2 signaling proteins known to guide cell migration: chemokines CCL3 and CCL21.

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

Larger clinical studies will be needed to confirm this approach of boosting immune responses and targeting cytomegalovirus in glioblastomas. Continued research into the mechanisms involved in the response to cancer vaccines — and how best to target cytomegalovirus and other tumor proteins — may also lead to further improvements.