The Development of a Synthetic Self-Adjuvanting Cancer Vaccine

Abstract

Cancer testis antigens (CTA) have demonstrated high immunogenicity towards multiple cancer types, and due to their restricted expression profile, they warrant further attention as potential vaccine candidates. Covalently attaching an adjuvant to an antigen is an effective strategy to induce a strong, targeted immune response. This thesis describes a robust synthetic method to palmitoylate CTA peptides with a di-palmitoyl-S-glyceryl cysteine residue (Pam2Cys). These adjuvants, known to effectively enhance the severity of an immune response, were covalently linked to the chosen CTA sequences to develop a self-adjuvanting, targeted cancer vaccine. Liposomes can provide adjuvant activity either by enhancing antigen delivery or by activating innate immune responses. To examine this, a CTA antigen bearing an N-terminal Cys was conjugated covalently to the outer envelope of liposome particles via conjugation to a lipid carrying an appropriate electrophilic headgroup. The palmitoylated CTA sequences with native Pam2Cys were also inserted into the lipid bilayer of the liposomes via the palmityl 'tails' and these strategies of adjuvant and antigen incorporation into the particle formulation compared. The immune responses generated by the self-adjuvanting CTA peptide vaccine constructs, self-adjuvanting CTA peptides formulated into liposomal vaccine formulations, and the liposomes carrying the conjugated peptide antigens onto outer envelope of the nanoparticles were examined in vivo using healthy mouse models.