An innovative approach using a tetanus booster to prime the immune system enhances the effect of a vaccine therapy for lethal brain tumors, dramatically improving patient survival, according to a study led by Duke Cancer Institute researchers.

Appearing in the March 11 journal Nature, the researchers not only present survival data for a small, randomized and blinded patient trial, but they also detail how the tetanus preconditioning technique works, providing a roadmap for enhancing dendritic cell immunotherapies that have shown promise treating the most lethal form of brain cancer.

“Patients with glioblastoma usually survive for little more than 1 year. However, in patients who received the immunotherapy, one-half lived nearly 5 years or longer from their diagnosis, so the findings are promising and significant,” says senior author John Sampson, MD, PhD, chief of the Division of Neurosurgery at Duke University Medical Center.

The researchers built on earlier findings that glioblastoma tumors harbor a strain of cytomegalovirus (CMV) that is not present in surrounding brain tissue, creating a natural target for immunotherapy.

One such targeted approach uses dendritic cells, which train the immune system to respond to specific pathogens. The Duke research team developed a process to extract white blood cells, boost the growth of dendritic cells, and load them with the viral antigens.

The dendritic cells were then injected back into patients, entered the lymph nodes, and stimulated an attack on the CMV present in the tumor tissue.

This immunotherapy worked well, but researchers sought a way to prime the immune system before infusion of dendritic cells. They chose a tetanus/diphtheria toxoid, a widely available and clinically approved vaccine, to precondition the injection site.

Researchers enrolled 12 brain tumor patients; one-half were randomly assigned to receive a tetanus booster and the other half a placebo injection. Within 24 hours, patients in both groups received the dendritic cell immunotherapy.

Patients who were randomized to the tetanus shot showed a significant increase in survival from the time of preconditioning than patients who received just the dendritic cell therapy, with one-half living from 51 to 101 months, compared with 11.6 months for the placebo group. One patient from the tetanus group continues to have no tumor growth and is still alive 8 years after the treatment.

“These findings have potential relevance for improving dendritic cell vaccines not only for patients with glioblastoma, but also in the immunologic targeting of other cancers,” says co-lead and co-corresponding author, Duane A. Mitchell, MD, PhD, who is currently director of the University of Florida brain tumor immunotherapy program. “We are obviously pursuing larger-scale confirmatory studies but are very encouraged by these data and the future applicability.”

The researchers used mouse studies to track how the immunotherapy worked. They identified a new role for an immune signaling protein called CCL3, which had previously been known for mediating other immune activities but had not been associated with creating increased migration of dendritic cells to the lymph nodes. The protein was found to work systemically, not just at the injection site.

“The fact that the mice and our patients who were given tetanus had elevated CCL3 prompted us to investigate the role of this protein in the mechanism, which in turn revealed that both CCL3 and the recall responses from tetanus boosting needed to work together to increase the migration of our vaccines,” says co-lead author Kristen A. Batich, a Duke MD/PhD candidate.

“Although dendritic cell vaccines have shown some promise in the treatment of patients with advanced cancers, including glioblastoma, the dynamics of this process have not been well understood,” Sampson says. “Our work identifies an immunologic interaction whereby recall responses to one antigen—tetanus—can influence the migratory capacity of dendritic cells loaded with different antigens—CMV.”

The researchers plan a new study to determine whether successful dendritic cell migration could be used as a prognostic indicator of patient survival.

“Our study indicates that dendritic cell migration to the lymph nodes can be improved significantly by preconditioning the vaccine site with a tetanus boost, and this appears to improve antitumor responses and prolonged survival,” Batich says.

In addition to Sampson, Batich, and Mitchell, study authors include Michael D. Gunn, Min-Nung Huang, Luis Sanchez-Perez, Smita K. Nair, Kendra L. Congdon, Elizabeth A. Reap, Gary E. Archer, Annick Desjardins, Allan H. Friedman, Henry S. Friedman, James E. Herndon II, April Coan, Roger E. McLendon, David A. Reardon, James J. Vredenburgh, and Darell D. Bigner.