Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer

Abstract

The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine [encoding transgenes for prostate-specific antigen (PSA) and 3 costimulatory molecules] in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3-5 also received intraprostatic rF-GM-CSF. Cohort 5 received additional subcutaneous boosters with rF-PSA-TRICOM and rF-GM-CSF. Patients had pre- and post-treatment prostate biopsies, and analyses of peripheral and intraprostatic immune cells were performed. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. The most common grade 2 adverse events were fever (38%) and subcutaneous injection site reactions (33%); the single grade 3 toxicity was transient fever. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4+ (p = 0.0002) and CD8+ (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Clinical trials examining clinical end points are warranted.

Fig. 1

Prostate-specific antigen results. a Waterfall plot of percentage change in serum prostate-specific antigen (PSA), comparing baseline to lowest on-study value. Plot excludes patients who were castration sensitive and on androgen deprivation therapy, as well as one patient with castration-resistant prostate cancer (CRPC) who had bicalutamide added to his GnRH agonist at time of enrollment. Filled bars = patients with castration-naïve prostate cancer (CNPC); empty bars = patients with CRPC. b–d Serum PSA trends of 3 patients with CNPC. Arrow start of study treatment. b Patient 5: 30 % decrease in PSA value. c Patient 6: 50 % decrease in PSA value. d Patient 11: 30 % decrease in PSA value. e Waterfall plot comparing percentage change from baseline to end-of-study PSA doubling time (DT). Plot excludes patients who were castration sensitive and on androgen deprivation therapy (ADT), as well as one patient with CRPC who was started on combined androgen blockade at time of enrollment. *Patient’s PSA DT was no longer measurable because PSA was decreasing. ^#Patient’s PSA was decreasing at enrollment but increased slightly on study. Filled bars = patients with CNPC; empty bars = patients with CRPC

Fig. 2

Paired t-test analysis of pre- and post-vaccination numbers of each cell type per high power field (hpf). Three random samples from each patient were stained and counted. Numbers indicate average of those samples. Graphs show median with standard deviation and p values. a CD4⁺, (b) CD8⁺. c–j CD4 and CD8 single staining in prostatic core biopsies taken pre- and post-vaccination. Positive cells show brown, membranous staining. Images 2c–d illustrate a pre-treatment biopsy sample stained for CD4⁺ at low (×20) and high (×60) power, respectively. Images 2e–f illustrate a pre-treatment biopsy sample stained for CD8⁺ at low (×20) and high (×60) power, respectively. The corresponding post-treatment biopsies are seen to the right. Images 2g, h illustrate a post-treatment biopsy sample stained for CD4⁺ at low (×20) and high (×60) power, respectively. Images 2i, j illustrate a post-treatment biopsy sample stained for CD8⁺ at low (×20) and high (×60) power, respectively