Initial development of an antiprostate cancer vaccine targeting PSA in PSA and HLA-A*0201/D(d) transgenic mice

This dissertation describes the initial experiments in the development of a prostate cancer immunotherapy that specifically targets the prostate specific antigen (PSA) expressed in 95% of prostatic adenocarcinomas. Previous literature reports demonstrated the induction of PSA specific, anti-tumor immunity in normal mice and PSA specific cytotoxic T lymphocytes (CTL) in PSA transgenic mice. Using a PSA transgenic mouse with prostate specific expression of PSA due to attaching the human PSA gene to the rat probasin promoter which directs prostate specific expression, the functionality of these PSA specific CTLs was investigated. Vaccination of PSA transgenic mice with the PSA expressing, human prostate cancer cell line, LNCaP, created a PSA specific response capable of inhibiting the growth of subsequently injected PSA expressing tumor cells. Efforts in the lab switched to a peptide focused approach to increase the strength of the induced immunity. Computer algorithms that predict putative MHC epitopes based on known binding motifs and competition assays produced a candidate list of eight, A*0201 restricted PSA peptides. Adding a ninth peptide based on published reports, these peptides were tested for their ability to induce a CTL response within HLA-A*0201/Dd (A2Dd) transgenic mice containing chimeric MHC molecules capable of presenting A*0201 restricted peptides while interacting with mouse T cells. Four peptides proved to be immunogenic and with the addition of another peptide with great similarity to one of the four peptides, these five peptides were used in protection assays to determine if a peptide pulsed dendritic cell vaccine could prevent the growth of injected PSA expressing tumor cells. Four of the peptides induced statistically significant protection and were found to not bind the native murine MHC class I molecules thus classifying these responses as quasihuman. The fifth peptide produced a trend towards protection and was found to cross react with the mouse MHC molecules indicating that the measured response was via either the mouse or human MHC molecules. These data demonstrate the induction of protective PSA responses in a setting where PSA is considered a self-antigen and the ability of PSA peptides to elicit protective anti-tumor immunity in a quasi-human setting.