Phase II Trial of a DNA Vaccine Encoding Prostatic Acid Phosphatase (pTVG-HP [MVI-816]) in Patients With Progressive, Nonmetastatic, Castration-Sensitive Prostate Cancer

Abstract

Purpose: We previously reported the safety and immunologic effects of a DNA vaccine (pTVG-HP [MVI-816]) encoding prostatic acid phosphatase (PAP) in patients with recurrent, nonmetastatic prostate cancer. The current trial evaluated the effects of this vaccine on metastatic progression.

Patients and methods: Ninety-nine patients with castration-sensitive prostate cancer and prostate-specific antigen (PSA) doubling time (DT) of less than 12 months were randomly assigned to treatment with either pTVG-HP co-administered intradermally with 200 μg granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant or 200 μg GM-CSF alone six times at 14-day intervals and then quarterly for 2 years. The primary end point was 2-year metastasis-free survival (MFS). Secondary and exploratory end points were median MFS, changes in PSA DT, immunologic effects, and changes in quantitative 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) imaging.

Results: Two-year MFS was not different between study arms (41.8% vaccine v 42.3%; P = .97). Changes in PSA DT and median MFS were not different between study arms (18.9 v 18.3 months; hazard ratio [HR], 1.6; P = .13). Preplanned subset analysis identified longer MFS in vaccine-treated patients with rapid (< 3 months) pretreatment PSA DT (12.0 v 6.1 months; n = 21; HR, 4.4; P = .03). PAP-specific T cells were detected in both cohorts, including multifunctional PAP-specific T-helper 1-biased T cells. Changes in total activity (total standardized uptake value) on 18F-NaF PET/CT from months 3 to 6 increased 50% in patients treated with GM-CSF alone and decreased 23% in patients treated with pTVG-HP (n = 31; P = .07).

Conclusion: pTVG-HP treatment did not demonstrate an overall increase in 2-year MFS in patients with castration-sensitive prostate cancer, with the possible exception of a subgroup with rapidly progressive disease. Prespecified 18F-NaF PET/CT imaging conducted in a subset of patients suggests that vaccination had detectable effects on micrometastatic bone disease. Additional trials using pTVG-HP in combination with PD-1 blockade are under way.

Trial registration: ClinicalTrials.gov NCT01341652.

Figures

FIG 1.

Schema and patient allocation. (A) Treatment schema and (B) CONSORT diagram. 18F-NaF, 18F-sodium fluoride; CT, computed tomography; GM-CSF, granulocyte-macrophage colony-stimulating factor; PET, positron emission tomography.

FIG 2.

Metastasis-free survival (MFS). (A) Kaplan-Meier plot of time to radiographic progression. Time to radiographic regression was defined as the time from random assignment to the date of documented radiographic progression or last available follow-up date. (B) Kaplan-Meier plots of time to radiographic progression for stratification cohorts of patients with pretreatment prostate-specific antigen (PSA) doubling time (DT) of less than 3 months, 3 to 6 months, and 6 to 12 months. Comparisons made by log-rank test, with P < .05 considered statistically significant. GM-CSF, granulocyte-macrophage colony-stimulating factor; HR, hazard ratio.

FIG 3.

Immunologic response: FluoroSpot (Cellular Technology Limited, Shaker Heights, OH) analysis. Cryopreserved peripheral blood mononuclear cells (PBMCs) from patients obtained at the indicated time points were stimulated in vitro with prostatic acid phosphatase (PAP) protein and evaluated by FluoroSpot for (A) PAP-specific interferon γ (IFN-γ) secretion or (B) PAP-specific secretion of IFN-γ, tumor necrosis factor-α, and granzyme B. Comparisons within treatment arms are made by nonparametric Wilcoxon signed rank test and between arms by nonparametric Wilcoxon rank sum test. All comparisons with P < .05 are shown. GM-CSF, granulocyte-macrophage colony-stimulating factor; SUV, standardized uptake value.

FIG 4.

18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) analysis. Box and whisker plots (median and interquartile range) for the (A) total number of lesions identified at each time point by 18F-NaF PET/CT, (B) numerical change in number of lesions detected between time points indicated, (C) total standardized uptake value (SUVtotal) of identified bone lesions at each time point, and (D) percent change in SUVtotal between the time points indicated. Comparisons were made by nonparametric Wilcoxon rank sum test. (E) Representative 14F-NaF PET/CT images from one patient. GM-CSF, granulocyte-macrophage colony-stimulating factor.