title: GLIPR1 tumor suppressor gene expressed by adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy.
abstract: BACKGROUND
  GLIPR1 is upregulated by p53 in prostate cancer cells and has preclinical antitumor activity. A phase I clinical trial was conducted to evaluate the safety and activity of the neoadjuvant intraprostatic injection of GLIPR1 expressing adenovirus for intermediate or high-risk localized prostate cancer before radical prostatectomy (RP).
  
  
  METHODS
  Eligible men had localized prostate cancer (T1-T2c) with Gleason score greater than or equal to 7 or prostate-specific antigen 10 ng/mL or more and were candidates for RP. Patients received the adenoviral vector expressing the GLIPR1 gene by a single injection into the prostate followed four weeks later by RP. Six viral particle (vp) dose levels were evaluated: 10(10), 5 × 10(10), 10(11), 5 × 10(11), 10(12), and 5 × 10(12) vp.
  
  
  RESULTS
  Nineteen patients with a median age of 64 years were recruited. Nine men had T1c, 4 had T2a, and 3 had T2b and T2c clinical stage. Toxicities included urinary tract infection (n = 3), flu-like syndrome (n = 3), fever (n = 1), dysuria (n = 1), and photophobia (n = 1). Laboratory toxicities were grade 1 elevated AST/ALT (n = 1) and elevations of PTT (n = 3, with 1 proven to be lupus anticoagulant). No pathologic complete remission was seen. Morphologic cytotoxic activity, induction of apoptosis, and nuclear p27(Kip1) upregulation were observed. Peripheral blood CD8(+), CD4(+), and CD3(+) T-lymphocytes were increased, with upregulation of their HLA-DR expression and elevations of serum IL-12.
  
  
  CONCLUSIONS
  The intraprostatic administration of GLIPR1 tumor suppressor gene expressed by an adenoviral vector was safe in men, with localized intermediate or high-risk prostate cancer preceding RP. Preliminary evidence of biologic antitumor activity and systemic immune response was documented.
authors.affiliation: Department of Medicine, Section of Medical Oncology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.forename: Rajul K
authors.initials: RK
authors.lastname: Jain
authors.forename: Gustavo E
authors.initials: GE
authors.lastname: Ayala
authors.forename: Shinji
authors.initials: S
authors.lastname: Kurosaka
authors.forename: Kohei
authors.initials: K
authors.lastname: Edamura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Chengzhen
authors.initials: C
authors.lastname: Ren
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Goltsov
authors.forename: Martha P
authors.initials: MP
authors.lastname: Mims
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Hayes
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Adrian
authors.initials: A
authors.lastname: Gee
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Miles
authors.forename: Dov
authors.initials: D
authors.lastname: Kadmon
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D018014:Gene Transfer Techniques; D016153:Genes, Suppressor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D012306:Risk
chemical_list: C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins