Adjuvant screen identifies DC modifying growth factor Flt3 ligand as candidate for prostate cancer DNA vaccine

Abstract

Prostate cancer is the most common type of cancer in men. Immunotherapies such as Sipuleucel-T have shown that stimulating the immune system to target the prostate is a viable therapeutic option. Inovio is a clinical-stage biotechnology company that uses DNA vaccines as a novel immunotherapy strategy. An advantage to plasmid DNA vaccine therapy is the ability to encode adjuvants within the vaccine in order to increase immunogenicity and efficacy. We conducted an adjuvant screen in BALB/c mice with 25 candidate plasmid encoded genetic adjuvants in combination with the prostate cancer specific tumor-associated antigen STEAP1. Antigen-specific T cell responses were measured by IFNg ELISpot. The screen revealed that the addition of a plasmid encoding dendritic cell (DC)-activating Fms-like tyrosine kinase 3 ligand (Flt3L) fused to an Fc domain, significantly increased antigen-specific T cells (p<0.001, 2.8 fold). Mice treated with Flt3L-Fc had an enhanced immune response to STEAP1 vaccination as early as 7 days post dose 1 (p<0.01, 2.4 fold), which developed into an enhanced memory response measured 12 weeks later (p<0.001, 8.5 fold). Flow cytometry showed that Flt3L-Fc increased DC populations at the site of injection and at the draining lymph node 8 days following the initial vaccination. DCs are considered the most potent antigen-presenting cells in the immune system and DCs at the tumor site have been shown to be critical for T cell immunity. Our data shows that enhancing DC populations and function through the use of a genetic adjuvant can enhance the immunogenicity of a DNA cancer vaccine. Future studies will assess the efficacy of Flt3L-Fc in combination with STEAP1 in a mouse tumor model.