DNA fusion vaccines enter the clinic

Abstract

Induction of effective immune attack on cancer cells in patients requires conversion of weak tumor antigens into strong immunogens. Our strategy employs genetic technology to create DNA vaccines containing tumor antigen sequences fused to microbial genes. The fused microbial protein engages local CD4+ T cells to provide help for anti-tumor immunity, and to reverse potential regulation. In this review, we focus on induction of CD8+ T cells able to kill target tumor cells. The DNA vaccines incorporate tumor-derived peptide sequences fused to an engineered domain of tetanus toxin. In multiple models, this design induces strong CD8+ T-cell responses, able to suppress tumor growth. For clinical relevance, we have used "humanized" mice expressing HLA-A2, successfully inducing cytolytic T-cell responses against a range of candidate human peptides. To overcome physical restriction in translating to patients, we have used electroporation. Clinical trials of patients with cancer are showing induction of responses, with preliminary indications of suppression of tumor growth and evidence for clinically manageable concomitant autoimmunity.

Fig. 1

The p. DOM-epitope plasmid design incorporates three components: the backbone of bacterial DNA, the tumor-derived target peptide (or protein) sequence, and microbial sequences to activate T-cell help, derived from Tetanus Toxin or from plant viral coat proteins

Fig. 2

The design of the p.DOM-epitope vaccines aimed to induce anti-tumor CD8+ T cells. The Fragment C of tetanus toxin has been engineered to include only the N-terminal domain (DOM 1) which contains the promiscuous p30 epitope able to induce T-cell help. The second domain (DOM 2) that contains potentially competitive MHC Class I (HLA-A2)-binding peptides has been removed. The tumor-derived target peptide sequence is then placed at the C-terminus of DOM 1