title: 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.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr., 8B09 MSC 1750, Bethesda, MD 20892, USA. gulleyj@mail.nih.gov
authors.forename: James L
authors.initials: JL
authors.lastname: Gulley
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heery
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Madan
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Walter
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Peter A
authors.initials: PA
authors.lastname: Pinto
mesh_terms: D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000235:genetics; D015331:Cohort Studies; D006801:Humans; D015552:Injections, Intralesional; D007610:Kallikreins / Q000097:blood / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics / Q000276:immunology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes
chemical_list: D019496:Cancer Vaccines; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen