Cancer vaccines self-sabotage by channeling immune attack to injection site
Cancer vaccines that attempt to stimulate an immune system assault fail because the killer T cells aimed at tumors instead find the vaccination site a more inviting target. A common substance used in many cancer vaccines to boost immune attack betrays the cause by facilitating a buildup of T cells at the vaccination site, which then summon more T cells to help with the perceived threat.
"Vaccines stimulate production of T cells primed to attack the target cancer, and there are many T cells in the bloodstream after vaccination. We found that only a few get to the tumor while many more are stuck at or double back to the vaccination site," said senior author Willem Overwijk, PhD, of The University of Texas MD Anderson Cancer Center's Department of Melanoma Medical Oncology.
This results in largely unscathed tumors while an overstimulated immune response can cause lesions at the injection site. The major culprit in this failure is incomplete Freund's adjuvant (IFA), which is a mineral oil-based adjuvant included in many vaccines to stoke the immune response.
"Switching to a saline-based adjuvant in a melanoma vaccine reversed the T cell effect in mice," Overwijk said, "Major accumulations of T cells gathered in tumors, shrinking them, with minimal T cell activity at the vaccination site."
Peptide antigens are available for almost all types of cancer, Overwijk said. A saline adjuvant could change the poor performance of cancer vaccines.
The research team studied the fate of melanoma-specific CD8-positive T cells after vaccination with gp100 peptide with and without IFA. Both vaccines increased levels of the desired T cells in the blood, but with IFA, the T cells dropped to nearly undetectable levels after three weeks and did not rebound even with an engineered virus-based booster. The vaccine that lacked IFA produced similar peak amounts of the T cells, a response that persisted over time.
T cells were fluorescently tagged to track them in the mouse model. Mice without IFA had the bulk of T cells light up in their tumors with minimal presence at the vaccination site. T cells built up at the vaccination site in mice that received IFA-based vaccine, with a tiny showing of T cells in the tumor.
The response duration was tested in gp100/IFA and control IFA vaccines. The antigen/IFA combination gathered and persisted at the vaccination site, where it could stimulate the proliferation of injected T cells 96 days after vaccination.
A vaccine based on a saline solution instead of IFA had antigens that cleared more quickly, but it did not spark the desired T cell response. When a combination of three stimulatory molecules (covax) was added to the saline/peptide vaccine, a strong T cell response was produced. This study was published in Nature Medicine (2013; doi:10.1038/nm.3105).