Immunotherapy of prostate cancer using novel synthetic DNA vaccines targeting multiple tumor antigens

Abstract

Prostate cancer is a prevalent cancer in men and consists of both indolent and aggressive phenotypes. While active surveillance is recommended for the former, current treatments for the latter include surgery, radiation, chemo and hormonal therapy. It has been observed that the recurrence in the treated patients is high and results in castration resistant prostate cancer for which treatment options are limited. This scenario has prompted us to consider immunotherapy with synthetic DNA vaccines, as this approach can generate antigen-specific tumor-killing immune cells. Given the multifocal and heterogeneous nature of prostate cancer, we hypothesized that synthetic DNA vaccines targeting different prostate specific antigens are likely to induce broader and improved immunity who are at high risk as well as advanced clinical stage of prostate cancer, compared to a single antigen approach. Utilizing a bioinformatics approach, synthetic enhanced DNA vaccine (SEV) constructs were generated against STEAP1, PAP, PARM1, PSCA, PCTA and PSP94. Synthetic enhanced vaccines for prostate cancer antigens were shown to elicit antigen-specific immune responses in mice and the anti-tumor activity was evident in a prostate tumor challenge mouse model. These studies support further evaluation of the DNA tools for immunotherapy of prostate cancer and perhaps other cancers.

A mAb against surface-expressed FSHR engineered to engage adaptive immunity for ovarian cancer immunotherapy

“…Immunoblotting. Protein extraction, denaturation, and Western blotting were performed as previously described (29,60,61). Membranes were blotted with anti-phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (9101, Cell Signaling) and anti-p44/42 MAPK (Erk1/2) (4695, Cell Signaling).…”

Current status and progress of the development of prostate cancer vaccines

“…Compared with other candidate vaccines, splenocytes of mice immunized with STEAP1 and PAP-SEV showed a lower immune response. The enhanced delivery of these DNA vaccines mediated by the electroporation of plasmid (EP) can produce PCAA-specific CD8+T cells and increase their levels in tumor microenvironments, thereby improving the survival of mice carrying prostate cancer 19 . Although it is often reported that EP can increase the immunogenicity of vaccines, the conversion of this technique into human trials is slightly 2-3 times higher than that of simple injection of naked DNA 20 .…”

STEAP1–4 (Six-Transmembrane Epithelial Antigen of the Prostate 1–4) and Their Clinical Implications for Prostate Cancer

“…Given its localization to surface cell–cell junctions, particularly that of the prostatic secretory epithelium, STEAP1 is a promising target for T-cell and antibody-based immunotherapy [ 61 , 62 ]. Because STEAP1 is overexpressed in malignant prostate tissue but expressed at low levels in normal prostate tissue, STEAP1 is an ideal therapeutic target ( Table 1 ) [ 59 , 60 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ].…”

“…In vitro cytotoxicity assays demonstrated that these epitopes induced strong CTL-mediated antitumor activity [ 80 ]. Other approaches for targeting STEAP in PCa include fusion protein vaccines, RNA–lipoplex vaccines, recombinant viral vaccines, DNA vaccines, and CAR-T cells [ 64 , 65 , 66 , 67 , 73 ]. These studies are promising, and there is much work to do before they can be translated into PCa therapeutics.…”