Multicenter Phase I Trial of a DNA Vaccine Encoding the Androgen Receptor Ligand-binding Domain (pTVG-AR, MVI-118) in Patients with Metastatic Prostate Cancer

Abstract

Purpose: Preclinical studies demonstrated that a DNA vaccine (pTVG-AR, MVI-118) encoding the androgen receptor ligand-binding domain (AR LBD) augmented antigen-specific CD8+ T cells, delayed prostate cancer progression and emergence of castration-resistant disease, and prolonged survival of tumor-bearing mice. This vaccine was evaluated in a multicenter phase I trial.

Patients and methods: Patients with metastatic castration-sensitive prostate cancer (mCSPC) who had recently begun androgen deprivation therapy were randomly assigned to receive pTVG-AR on one of two treatment schedules over one year, and with or without GM-CSF as a vaccine adjuvant. Patients were followed for 18 months. Primary objectives were safety and immune response. Secondary objectives included median time to PSA progression, and 18-month PSA-PFS (PPFS).

Results: Forty patients were enrolled at three centers. Twenty-seven patients completed treatment and 18 months of follow-up. Eleven patients (28%) had a PSA progression event before the 18-month time point. No grade 3 or 4 adverse events were observed. Of 30 patients with samples available for immune analysis, 14 (47%) developed Th1-type immunity to the AR LBD, as determined by IFNγ and/or granzyme B ELISPOT. Persistent IFNγ immune responses were observed irrespective of GM-CSF adjuvant. Patients who developed T-cell immunity had a significantly prolonged PPFS compared with patients without immunity (HR = 0.01; 95% CI, 0.0-0.21; P = 0.003).

Conclusions: pTVG-AR was safe and immunologically active in patients with mCSPC. Association between immunity and PPFS suggests that treatment may delay the time to castration resistance, consistent with preclinical findings, and will be prospectively evaluated in future trials.See related commentary by Shenderov and Antonarakis, p. 5056.

Trial registration: ClinicalTrials.gov NCT02411786.

Conflict of interest statement

Conflicts of Interest: DGM has ownership interest, has received research support, and serves as consultant to Madison Vaccines, Inc. DGM and BMO have intellectual property related to this content licensed to Madison Vaccines, Inc. The other authors have no relevant potential conflicts of interest.

©2020 American Association for Cancer Research.

Figures

Figure 1:

Schema and patient allocation: Shown is the CONSORT diagram (panel A) and treatment schema (panel B).

Figure 2:

T-cell immunological response: PBMC from 30 patients treated at one center were evaluated in real time at the indicated time points for antigen-specific IFNγ (panel A) or granzyme B (panel B) secretion. PBMC were stimulated in vitro with peptides spanning the amino acid sequence of the AR LBD or PSA, or tetanus toxoid, and evaluated by ELISPOT. A positive immune response (red) was defined as an antigen-specific response (statistically higher than the media-only control, p<0.05 by t-test) that was at least 3-fold higher than pre-treatment and with a frequency >1:100,000 cells. Black squares indicate a time point where an assessment was performed, but in which immune response criteria were not met. White squares indicate time points where no data were collected. Patients with at least two “positive” responses post-treatment were defined as immune “responders.”

Figure 3:

T-cell immunological response over time: Panel A: IFNγ ELISPOT data as shown in Figure 2 were plotted over time, subtracting the pre-treatment value, to evaluate the magnitude and durability of immunity over time. Panel B: Immune response over time was plotted as “area under the curve,” and evaluated with respect to treatment arm. Lines show median and interquartile range. Comparison between arms was made by t test.

Figure 4:

Clinical outcomes: Time to progression (percentage free from castration resistance, right panels, and percentage free from first PSA rise, left panels) were evaluated from study start date in patients treated on arms 1 and 2 (no GM-CSF) versus arms 3 and 4 (with GM-CSF) (panel A), or in patients treated on arms 1 and 3 (schedule 1) versus arms 2 and 4 (schedule 2) (panel B). Time to castration-resistance (left panel) and time to first PSA rise (right panel) were also evaluated with respect to whether patients developed IFNγ and/or granzyme B T-cell immune response to the AR LBD target (panel C).