TARP vaccination is associated with slowing in PSA velocity and decreasing tumor growth rates in patients with Stage D0 prostate cancer

Abstract

T-cell receptor alternate reading frame protein (TARP) is a 58-residue protein over-expressed in prostate and breast cancer. We investigated TARP peptide vaccination's impact on the rise in PSA (expressed as Slope Log(PSA) or PSA Doubling Time (PSADT)), validated tumor growth measures, and tumor growth rate in men with Stage D0 prostate cancer. HLA-A*0201 positive men were randomized to receive epitope-enhanced (29-37-9V) and wild-type (27-35) TARP peptides administered as a Montanide/GM-CSF peptide emulsion or as an autologous peptide-pulsed dendritic cell vaccine every 3 weeks for a total of five vaccinations with an optional 6th dose of vaccine at 36 weeks based on immune response or PSADT criteria with a booster dose of vaccine for all patients at 48 and 96 weeks. 41 patients enrolled with median on-study duration of 75 weeks at the time of this analysis. Seventy-two percent of patients reaching 24 weeks and 74% reaching 48 weeks had a decreased Slope Log(PSA) compared to their pre-vaccination baseline (p = 0.0012 and p = 0.0004 for comparison of overall changes in Slope Log(PSA), respectively). TARP vaccination also resulted in a 50% decrease in median tumor growth rate (g): pre-vaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p = 0.003). 80% of subjects exhibited new vaccine-induced TARP-specific IFNγ ELISPOT responses but they did not correlate with decreases in Slope Log(PSA). Thus, vaccination with TARP peptides resulted in significant slowing in PSA velocity and reduction in tumor growth rate in a majority of patients with PSA biochemical recurrence.

Keywords: PSA biochemical recurrence; Prostate cancer; TARP; therapeutic cancer vaccine.

Figure 1.

Clinical trial design. HLA-A*0201 positive men with Stage D0 prostate cancer and a PSADT > 3 mo and < 15 mo were randomized 1:1 to receive a primary vaccination series of five TARP peptide vaccines administered q 3 weeks with a conditional booster dose at Week 36 depending on immune reactivity and PSADT at Week 24. Subsequent study amendment allowed booster doses for all patients at Weeks 48 and 96.

Figure 2.

Representative schematic of PSADT relationship to Slope Log(PSA) (A), PSA response to TARP vaccination with Montanide ISA 51-GM-CSF (B) and PSA response to TARP autologous DC vaccination (C). Red arrow in (B) and (C) represents estimated PSA trajectory within the 48 weeks prior to study entry.

Figure 3.

Waterfall plot of difference in pre-treatment Slope Log(PSA) versus post-TARP vaccination Slope Log(PSA) at 3–24 weeks (A) and at 3–48 weeks (B).

Figure 4.

Changes in tumor growth rate constants (g) calculated from fitting the PSA curves to an exponential tumor growth model. Comparison of the median growth rate constant (the median is the bold horizontal line within the gray shaded box that represents the 25th percentile [lower quartile] to 75th percentile [upper quartile]) of the estimated g of individual subjects pre- (pink dots) and post-TARP vaccination (green dots) (A). For change in tumor growth rate constant over time (B), each black dot at a given time point on treatment is the mean of calculated growth rates to that time point for all patients on study at that time point; the blue vertical lines with horizontal cross hatches represent 95% confidence intervals for each respective mean. Note the marked differences between days 42 and 147/231, despite very little patient attrition, excluding selection of patients with more indolent disease as a reason for the declines.

Figure 5.

TARP-specific immunological responses. Shown are the mean spot responses per 106 PBMC following a 7 d in vitro stimulation (IVS) IFN-γ ELISPOT assay to vaccine (WT27-35, EE29-37-9V) and non-vaccine (WT29-37) TARP peptides in subjects with a positive difference in Slope Log(PSA) (non-responders) and a negative difference in Slope Log(PSA) (responders) following TARP vaccination compared to pre-vaccine treatment, at Week 24 (A) and Week 48 (B).