Anti-tumor activity of a T-helper 1 multiantigen vaccine in a murine model of prostate cancer

Abstract

Prostate cancer is one of the few malignancies that includes vaccination as a treatment modality. Elements of an effective cancer vaccine should include the ability to elicit a Type I T-cell response and target multiple antigenic proteins expressed early in the disease. Using existing gene datasets encompassing normal prostate tissue and tumors with Gleason Score ≤ 6 and ≥ 8, 10 genes were identified that were upregulated and conserved in prostate cancer regardless of the aggressiveness of disease. These genes encoded proteins also expressed in prostatic intraepithelial neoplasia. Putative Class II epitopes derived from these proteins were predicted by a combination of algorithms and, using human peripheral blood, epitopes which selectively elicited IFN-γ or IL-10 dominant antigen specific cytokine secretion were determined. Th1 selective epitopes were identified for eight antigens. Epitopes from three antigens elicited Th1 dominant immunity in mice; PSMA, HPN, and AMACR. Each single antigen vaccine demonstrated significant anti-tumor activity inhibiting growth of implanted Myc-Cap cells after immunization as compared to control. Immunization with the combination of antigens, however, was superior to each alone in controlling tumor growth. When vaccination occurred simultaneously to tumor implant, multiantigen immunized mice had significantly smaller tumors than controls (p = 0.002) and a significantly improved overall survival (p = 0.0006). This multiantigen vaccine shows anti-tumor activity in a murine model of prostate cancer.

Figure 1

Flow diagram describing multiantigen prostate cancer vaccine antigen selection.

Figure 2

A subunit vaccine, containing only Th1-selective epitopes, is necessary to inhibit prostate tumor growth. (A) Mean (± SEM) corrected spots per well (CSPW) for IFN-γ (orange) and IL-10 (blue) in mice vaccinated with the peptide pool PSMA-p397/p216/p181 or PSMA-p582/p570/p466. HIVp52 is used as a negative control peptide. n = 7–8 mice/group; *p < 0.05, **p < 0.01, ***p < 0.001. (B) Mean (± SEM) tumor volume (mm3) from mice immunized with the adjuvant alone or the peptide pool PSMA-p582/p570/p466 (PSMA Th1 vaccine) or the peptide pool PSMA-p397/p216/p181 (PSMA Th2 vaccine) or the combination of both vaccines (Th1 + Th2). n = 15 mice/group; ***p < 0.001.

Figure 3

A Th1 selective multiantigen vaccine, administered prior to tumor implant, is effective in inhibiting prostate cancer growth. Tumor volume (mm³) from mice vaccinated with (A) adjuvant alone or the peptide pools derived from (B) AMACR, (C) PSMA, (D) HPN or (E) a combination of the epitopes (multiantigen vaccine). Volume for individual mice (n = 15/group) is presented in thin lines and the mean volume is presented as the thick line. **p < 0.01; ****p < 0.0001.

Figure 4

The Th1 selective multiantigen vaccine, administered after tumor implant, limits prostate cancer growth and increases overall survival. (A) Tumor volume from mice immunized with adjuvant alone (orange lines) or the multi-antigen vaccine (blue lines). Volume for individual mice (n = 15/group) is presented in thin lines and the mean volume is presented as the thick line. Arrows indicate when the vaccines were administered. (B) Kaplan Meir curve for percent survival from mice immunized with adjuvant alone (orange line) or the multiantigen (blue line). n = 15 mice/group; ***p < 0.01, ****p < 0.0001.