Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer

Abstract

Purpose: Prostatic acid phosphatase (PAP) is a prostate tumor antigen. We have previously demonstrated that a DNA vaccine encoding PAP can elicit antigen-specific CD8+ T cells in rodents. We report here the results of a phase I/IIa trial conducted with a DNA vaccine encoding human PAP in patients with stage D0 prostate cancer.

Patients and methods: Twenty-two patients were treated in a dose-escalation trial with 100 microg, 500 microg, or 1,500 microg plasmid DNA, coadministered intradermally with 200 microg granulocyte-macrophage colony-stimulating factor as a vaccine adjuvant, six times at 14-day intervals. All patients were observed for 1 year after treatment.

Results: No significant adverse events were observed. Three (14%) of 22 patients developed PAP-specific IFN gamma-secreting CD8+ T-cells immediately after the treatment course, as determined by enzyme-linked immunospot. Nine (41%) of 22 patients developed PAP-specific CD4+ and/or CD8+ T-cell proliferation. Antibody responses to PAP were not detected. Overall, the prostate-specific antigen (PSA) doubling time was observed to increase from a median 6.5 months pretreatment to 8.5 months on-treatment (P = .033), and 9.3 months in the 1-year post-treatment period (P = .054).

Conclusion: The demonstration that a DNA vaccine encoding PAP is safe, elicits an antigen-specific T-cell response, and may be associated with an increased PSA doubling time suggests that a multi-institutional phase II trial designed to evaluate clinical efficacy is warranted.

Fig 1.

Immunological response. CD8+ interferon gamma (IFNγ) enzyme-linked immunospot (ELISPOT): CD8+ T cells purified from peripheral blood mononuclear cells pretreatment or post-treatment were cocultured with (A) prostatic acid phosphatase (PAP) or (B) tetanus toxoid (Tet) and autologous antigen-presenting cells, and assessed for IFNγ secretion by ELISPOT. (*) Significant responses (P < .05, two-sided t-test).

Fig 2.

Antigen-specific T-cell proliferation. Peripheral blood mononuclear cells from patient 6 obtained preimmunization or postimmunization were cultured in the presence of 2 μg/mL prostatic acid phosphatase (PAP), 250 ng/mL tetanus toxoid (Tet), 2.5 μg/mL phytohemaglutinin (PHA), or media only (no antigen) for 96 hours. Ten μmol/L bromodeoxyuridine (BrdU) was added for the last 8 hours of culture before flow cytometric analysis. (A) CD4+ or (B) CD8+ T cells costaining for BrdU. The x-axis in each graph shows BrdU staining and the numbers represent the percentage of BrdU+ events among CD4+ or CD8+ cells. FITC, fluorescein isothiocyanate.

Fig 3.

Immunological response: antigen-specific T-cell proliferation. Assessment of antigen-specific T-cell proliferation was conducted as in Figure 2. Shown are the proliferation indices (% bromodeoxyuridine [BrdU] + events under antigen-stimulation condition/% BrdU+ events for media only) pre- and post-treatment for (A, B) prostatic acid phosphatase (PAP) and (C, D) tetanus (Tet). (A, C) CD4+ T-cell proliferation and (B, D) CD8+ T-cell proliferation.

Fig 4.

Prostate-specific antigen (PSA) responses. (A) Log-transformed serum PSA values from all patients obtained over time with respect to beginning the vaccination series. (B) PSA doubling time (DT) values were calculated for all patients pretreatment, on-treatment, and post-treatment. Negative and high positive (> 36 months) PSA DT estimates were censored at 36 months. (C) Boxplots for distributions of changes in PSA DT from the pretreatment to the on-treatment period and from the pretreatment to the post-treatment follow-up period are shown. The horizontal bold line shows the median while the box shows the 25th and the 75th percentiles of the changes in PSA DT values.