Targeting novel antigens for prostate cancer treatment: focus on prostate-specific membrane antigen

Abstract

Prostate-specific membrane antigen (PSMA) is a relatively omnipresent, but unique Type II dimeric transmembrane protein with a multiplicity of functions and has been shown to be a reasonable target for immunological approaches such as vaccines or more directed therapy with radioactively labelled monoclonal antibodies against PSMA. Given the abundance of various glycoprotein and carbohydrate antigens expressed on the surface of prostate cancer cells and cell lines, PSMA stands out as another 'self' antigen which is not only expressed on cancer cells, but on neovasculature. Although vaccines are varied in their design and target goal, recent technology has afforded researchers the opportunity to induce recruitment of multiple effector cell populations, cytokines and factors which can elicit both cellular and humoral responses. This review serves to present unique approaches in vaccine development which can induce immunological responsiveness with potential impact on disease progression and to introduce PSMA as a potential target for multimodality therapies.

Figures

Figure 1

Globular nature of PSMA and the amino acids (aa) which make up the various domains. Note the distinct transmembrane domain (B), the intracellular cytoplasmic domain (A), the catalytic binding site (E) and extracellular domains C, D, E, F. [Domain A: aa 1 - 19; Domain B: aa 20 - 39; Domain C: aa 40 - 144; domain D: aa 173 - 248; Domain E: aa 275 - 596; Domain F: aa 597 - 756]. PSMA: Prostate-specific membrane antigen; PSM’: RNA splice variant of PSMA.

Figure 2

Immunogenicity of rsPSMA vaccine. Compared with other adjuvants, such as the saponin QS-21, a much more vigorous response was seen using alum [48]. ELISA: Enzyme-linked immunosorbent assay; FACS: Fluorescence-activated cell sorting; PSMA: Prostate-specific membrane antigen.

Figure 3

Strategy for the VRP-PSMA vaccine currently under clinical development. PSMA: Prostate-specific membrane antigen; VRP: Vaccine replicon particle.

Figure 4

A) VRP generate potent cellular immune responses to PSMA in vivo. BALB/c mice were inoculated s.c in the footpad three times at 2-week intervals with PSMA-VRPs. CD8+ T cells were isolated from splenocytes using Miltenyi MACS columns. T cells and syngeneic CT26-PSMA stimulator cells were added to ELISPOT wells coated with anti-murine IFN-γ capture antibody. After 20 hour incubation, cells were washed off and IFN-γ spots developed with detection antibody and HRP catalysis [49]. B) VRP generate potent humoral immune responses to PSMA in vivo. Groups of 5 BALB/c mice were inoculated subcutaneous in the footpad 3 times at 2-week intervals with PSMA-VRP. Two weeks after the final dose, serum was separated from blood, and used at 1:100 dilution in FACS analysis with 3T3 cells expressing human PSMA [49]. ELISPOT: Enzyme-linked immunoSPOT; FACS: Fluorescence-activated cell sorting; HRP: Horse radish peroxidase; IFN: Interferon; MFI: Mean fluorescence intensity; PSMA: Prostate-specific membrane antigen; VRP: Vaccine replicon particle.