Phase 2 trial of T-cell activation using MVI-816 and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)

Abstract

Background: We previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report the final analysis of this trial following two additional treatment arms in which patients with mCRPC continued concurrent treatment until progression.

Materials and methods: Patients with mCRPC were treated with MVI-816 and pembrolizumab every 3 weeks (arm 3, n=20) or MVI-816 every 2 weeks and pembrolizumab every 4 weeks (arm 4, n=20). The primary objectives were safety, 6-month progression-free survival (PFS), median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations.

Results: In 25 patients with measurable disease, there were no complete response and one confirmed partial response in a patient who subsequently found to have an MSI^hi tumor. 4/40 patients (10%) had a prostate-specific antigen decline >50%. The estimated overall radiographic PFS rate at 6 months was 47.2% (44.4% arm 3, 61.5% arm 4). Accounting for all off-study events, overall median time on treatment was 5.6 months (95% CI: 5.4 to 10.8 months), 5.6 months for arm 3 and 8.1 months for arm 4 (p=0.64). Thirty-two per cent of patients remained on trial beyond 6 months without progression. Median overall survival was 22.9 (95% CI: 16.2 to 25.6) months. One grade 4 event (hyperglycemia) was observed. Immune-related adverse events (irAEs) >grade 1 were observed in 42% of patients overall. Interferon-γ and/or granzyme B immune response to prostatic acid phosphatase was detected in 2/20 patients in arm 3 and 6/20 patients in arm 4. Plasma cytokines associated with immune activation and CD8+ T-cell recruitment were augmented at weeks 6 and 12. The development of irAE was significantly associated with a prolonged time on treatment (HR=0.42, p=0.003). Baseline DNA homologous recombination repair mutations were not associated with longer time to progression.

Conclusions: Findings here demonstrate that combining programmed cell death 1 blockade with MVI-816 is safe, can augment tumor-specific T cells, and can result in a favorable 6-month disease control rate. Correlative studies suggest T-cell activation by vaccination is critical to the mechanism of action of this combination. Future randomized clinical trials are needed to validate these findings.

Trial registration number: NCT02499835.

Keywords: clinical trials, phase II as topic; costimulatory and inhibitory T-cell receptors; immunogenicity, vaccine; prostatic neoplasms.

Figure 1

Treatment schema for the original study arms evaluating treatment sequence (arms 1 and 2), and the arms evaluating treatment until progression (arms 3 and 4). pTVG-HP, DNA vaccine encoding prostatic acid phosphatase.

Figure 2

Immunological response: interferon-γ (IFN-γ) and granzyme B (GrzB) fluorescent ELISpot. Peripheral blood mononuclear cells (PBMCs) were collected from subjects (n=19, arm 3; n=20, arm 4) at baseline, 6 weeks, 12 weeks, and 24 weeks and evaluated for antigen-specific IFN-γ or GrzB secretion by fluorescent ELISpot. Shown are the spot-forming units (SFUs) for IFN-γ secretion (top panels) or GrzB secretion (bottom panels) following stimulation with a prostatic acid phosphatase (PAP) peptide library, PSA peptide library (non-specific control), or tetanus (positive control) for each patient. Patients treated in arm 3 are colored red, and patients treated in arm 4 are colored blue.

Figure 3

Treatment elicits increases in serum cytokines and chemokines. Plasma obtained from patients prior to treatment, and at weeks 6 and 12 of treatment, were evaluated for 35 cytokines and chemokines by multiplex Luminex assay. Shown are the changes in concentration from baseline for each patient, grouped by study arm (arm 1=green, arm 2=purple, arm 3=red, arm 4=blue), for those cytokines with significant change over time (by mixed-effects model): (A) G-CSF, (B) CXCL9, (C) CXCL10, (D) IFNα, (E) IL-2R, (F) IL-12, (G) MCP-1 (CCL2), (H) IL-1β, and (I) IL-2. (J) IFN-γ was below the level of detection for this multiplex assay and was separately measured from pretreatment to week 6 or pretreatment to week 12 by ELISA, with statistical comparison by paired t-test.

Figure 4

Clinical effects. (A) Serum PSA values were collected from all individuals prior to treatment and over the course of treatment. Shown are the best percentage change in serum PSA from day 1. Red lines show individual patients treated in arm 3, and blue lines show individual patients treated in arm 4. The horizontal line indicates 50% decrease from baseline. Asterisks indicate those individuals with immune response to prostatic acid phosphatase (PAP). (B) Shown are the best percentage change in tumor volume for 25 individuals in all treatment arms who had measurable disease, with the horizontal line indicating 30% decline. Asterisks indicate those individuals with immune response to PAP. (C) Swimmer plot showing the time on trial for all study patients. Asterisks indicate time of PSA progression, and open circles indicate radiographic progression. Triangles indicate those individuals with baseline DNA homologous recombination repair (HRR) mutations (n=10) or MSI-high tumors (n=2). The vertical line indicates 6 months.

Figure 5

Time on trial correlative analyses. Time on trial was assessed with respect to the development of grade 2 or higher immune-related adverse events (irAEs, A), T-cell immune response to prostatic acid phosphatase (B), increases in serum interferon-IFN-γ (C), and the presence of baseline homologous recombination repair (HRR) mutations or MSI-high tumors (D). Statistical comparisons are made using a log-rank test, with p<0.05 considered statistically significant.