643. Various Forms of CD40L Encoded as an Immune Plasmid Adjuvant Generate Unique Anti-Cancer DNA Vaccine Induced Responses

Abstract

The use of immune plasmid adjuvants encoding cytokine, chemokine or immune modulators to tailor the vaccine induced response is a strength of DNA vaccine approaches. This has been established through the recent HVTN080 trial which demonstrated the potency of pIL-12 in increasing cellular responses above that of DNA only vaccination. Due to its role in both innate and adaptive immunity, the co-delivery of plasmid encoded CD40 ligand (CD40L) could increase DNA vaccine responses. In its natural form, CD40L can occur as either a surface bound form or a cleaved/solubilized form. Thus, we sought to determine if different forms of pCD40L can influence cellular and humoral responses when co-delivered with a HPV16 DNA vaccine expressing the oncogenic proteins E6 and E7. Mice were immunized with HPV DNA with or without synthetic optimized plasmids expressing various forms of CD40L. Mice which received the soluble form of CD40L (sCD40L) exhibited significantly higher antigen specific CD8+ T cell responses including IFN-γ, IL-2 and TNF-α expression. These responses were maintained into memory. On the other hand, the surface bound as well as the wild type form blunted the vaccine induced responses compared to vaccine alone. Time course analysis revealed that 11 days after primary immunization, CD8+ tetramer specific (H-2Db HPV16 E7 (RAHYNIVTF)) T cells in mice immunized with sCD40L averaged around 18% compared to vaccine alone at 4%. These responses were partially dependent on CD4+ T cell help. Upon therapeutic tumor challenge, mice immunized with sCD40L displayed significant tumor regression compared to vaccine alone or naive animals. We have also seen similar vaccine induced immune responses when sCD40L was combined with an HIV Envelope expressing DNA vaccine as well as an H1N1 flu DNA vaccine. These results demonstrate the power of using an immune plasmid adjuvant encoding a synthetic optimized sCD40L in a DNA vaccine. Additional studies in other models are important for this approach to be considered for possible clinical development.