title: A phase I dose escalation trial of vaccine replicon particles (VRP) expressing prostate-specific membrane antigen (PSMA) in subjects with prostate cancer.
abstract: PSMA-VRP is a propagation defective, viral replicon vector system encoding PSMA under phase I evaluation for patients with castration resistant metastatic prostate cancer (CRPC). The product is derived from an attenuated strain of the alphavirus, Venezuelan Equine Encephalitis (VEE) virus, and incorporates multiple redundant safety features. In this first in human trial, two cohorts of 3 patients with CRPC metastatic to bone were treated with up to five doses of either 0.9×10(7)IU or 0.36×10(8)IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18, followed by an expansion cohort of 6 patients treated with 0.36×10(8)IU of PSMA-VRP at weeks 1, 4, 7, 10 and 18. No toxicities were observed. In the first dose cohort, no PSMA specific cellular immune responses were seen but weak PSMA-specific signals were observed by ELISA. The remaining 9 patients, which included the higher cohort and the extension cohort, had no PSMA specific cellular responses. PSMA-VRP was well-tolerated at both doses. While there did not appear to be clinical benefit nor robust immune signals at the two doses studied, neutralizing antibodies were produced by both cohorts suggesting that dosing was suboptimal.
authors.affiliation: Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. slovins@mskcc.org
authors.forename: Susan F
authors.initials: SF
authors.lastname: Slovin
authors.forename: Marissa
authors.initials: M
authors.lastname: Kehoe
authors.forename: Robert
authors.initials: R
authors.lastname: Durso
authors.forename: Celina
authors.initials: C
authors.lastname: Fernandez
authors.forename: William
authors.initials: W
authors.lastname: Olson
authors.forename: Jian P
authors.initials: JP
authors.lastname: Gao
authors.forename: Robert
authors.initials: R
authors.lastname: Israel
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
authors.forename: Stephen
authors.initials: S
authors.lastname: Morris
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing / Q000097:blood; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D004685:Encephalomyelitis, Venezuelan Equine / Q000235:genetics; D005822:Genetic Vectors; D043425:Glutamate Carboxypeptidase II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000628:therapy*; D012093:Replicon; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000954:Antigens, Surface; D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II