Developing DNA vaccines against the cancer-related prostrate-specific membrane antigen

Abstract

Vaccines are able to activate many compartments of the immune system in murine settings of infectious diseases and cancer. However, they have thus far had limited success in human trials. The two major problems for cancer are the weak immunogenicity of known target antigens and potential immune tolerance. To overcome these, our laboratory has developed novel DNA fusion vaccines encoding tumour antigens fused to a pathogen derived sequence from tetanus toxin. The strategy is to activate linked T-cell help from the large anti-microbial repertoire for anti-tumour immunity by using the entire or a partial sequence of Fragment C (FrC) of tetanus toxin. The aim of this study was to investigate the potential of the DNA fusion vaccine strategy for prostate cancer (PCa). PCa cells express a number of antigens that may serve as targets for vaccine-based therapeutic strategies. The prostate-specific membrane antigen (PSMA) tumour antigen is an attractive immunotherapeutic target due to the several-fold increased expression in the cancer as well as restricted expression in other tissues. PSMA-derived HLA-A2-binding peptides have been used in clinical trials despite limited knowledge of MHC class I-associated expression by tumour cells, a pre-requisite for successful targeting by cytotoxic T lymphocytes (CTL). To address this, DNA fusion vaccines in which discrete human PSMA-derived HLA-A2-binding epitope sequences (PSMA4, PSMA27, PSMA663 and PSMA711) are genetically fused to a domain (DOM) from FrC were made. The fusion vaccines were tested for their ability to induce epitope specific CD8+ T cells in HLA-A2 (HHD) transgenic mice. CD8+ T-cell responses against the specific human PSMA epitopes were induced, as assessed by ex vivo IFNy ELISPOT and in vitro CTL killing assays. Processing and presentation of the four peptides by tumour cells from an endogenous route, and tumour cell killing by CTL were shown. For PSMA711, only high avidity CTL could kill target cells, suggesting this peptide is presented at lower levels. These pre-clinical data will form the basis for the testing of the vaccines in patients. Full-length vaccines may also prime CD8+ T cells and would be applicable to patients of all MHC Class I haplotypes. However, we show that only low levels of CD8+ T cell immunity are generated by the full-length human PSMA vaccine. The work presented therefore does not support the full-length vaccine approach and demonstrates the superiority of our novel vaccine design for priming CD8+ T cells. To address the question of tolerance, a DOM fusion vaccine encoding the mouse PSMA MHC class I-binding peptide, mPSMA636, was created. This vaccine successfully overcame tolerance in mice to prime peptide-specific CD8+ T cells that effectively lysed mouse PSMA-expressing tumour cells in vitro.

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