Tetanus-Diphtheria Toxin May Boost Glioblastoma Dendritic Cell Vaccine Efficacy

Patients with glioblastoma multiforme may derive greater benefit from dendritic cell immunotherapy if given a tetanus–diphtheria vaccine booster directly beforehand

medwireNews: Giving a tetanus–diphtheria toxoid (Td) booster vaccination before dendritic cell (DC) immunotherapy may significantly increase survival in patients with newly diagnosed glioblastoma multiforme (GBM), research published in Nature suggests.

The study included 12 patients who had completed surgery and chemotherapy for GBM before repeat vaccination with DCs loaded with the phosphoprotein (pp)65 viral Antigen expressed by GBM cells.

DCs that reach the lymph nodes activate T cells to induce an anti-tumour immune response, explain Duane Mitchell, from Duke University Medical Center in Durham, North Carolina, USA, and co-authors.

The six patients who were vaccinated with a Td booster before DC vaccination had significantly greater accumulation of DCs in vaccine site-draining lymph nodes than those not given Td. Td-treated patients also showed a longer and greater pp65-specific T-cell response than controls.

Median progression-free and overall survival in the whole patient population was 10.8 and 18.5 months, respectively. Both outcomes were significantly longer in Td-treated patients than controls, at a median of 11.6 versus greater than 40 months, with three censored patients in the Td cohort alive and free from progression after more than 36.6 months.

Moreover, the percentage of migration of DCs was significantly associated with progression-free and overall survival, with a hazard ratio of 0.85 and 0.82 for each 1% increase in lymph node uptake.  

The researchers used a mouse model to test their findings and elucidated that the increased transport of antigen-loaded DCs to the lymph nodes was dependent on Td-specific memory CD4+ cells. Although the mice were preconditioned on one side only, the effect was systemic and tied to rapid induction of the cytokine CCL3 after Td exposure.

“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," Duane Mitchell commented in a press release.

"We are obviously pursuing larger-scale confirmatory studies, but are very encouraged by these data and the future applicability."

Rachel Lubong Sabado and Nina Bhardwaj, from Icahn School of Medicine at Mount Sinai, New York, USA, say in an accompanying comment that the results “provide a tantalizing approach to improving suboptimal DC vaccines.”

However, they note that further research is required to confirm the relationship between T-cell response and survival, and to determine whether all patients in the trial had pp65 protein-expressing GBM, as well as investigate the impact of other factors on vaccine efficacy, such as prior chemotherapy.

Nevertheless, they conclude: “Pre-conditioning and activating DC vaccines more potently, combining vaccines with agents to counteract factors that inhibit tumour-specific immune responses, and targeting DC vaccines directly to the tumour are all approaches with the potential to further enhance vaccine efficacy.”

References

Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 2015; Advance online publication 11 March. doi:10.1038/nature14320

Lubong Sabado R, Bhardwaj N. Dendritic-cell vaccines on the move. Nature 2015; Advance online publication 11 March. doi:10.1038/nature14211

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