GLIPR1 tumor suppressor gene expressed by adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy
Mené sur 19 patients atteints d'un cancer localisé de la prostate à haut risque (âge médian : 64 ans), cet essai de phase I évalue l'activité antitumorale et la toxicité d'un traitement néoadjuvant consistant en une injection intraprostatique d'un adénovirus exprimant GLIPR1, un gène suppresseur de tumeurs, quatre semaines avant une prostatectomie radicale
Purpose: GLIPR1 is up-regulated by p53 in prostate cancer (PCa) cells and has preclinical anti-tumor activity. A phase I clinical trial was conducted to evaluate the safety and activity of the neoadjuvant intraprostatic injection of GLIPR1 expressing adenovirus for high-risk localized PCa before radical prostatectomy (RP). Experimental Design: Eligible men had localized PCa (T1-T2c) with Gleason score ≥7 or PSA ≥ 10 ng/ml, and were candidates for RP. Patients received the adenoviral vector expressing the GLIPR1 gene by a single injection into the prostate followed 4 weeks later by RP. Six viral particle dose levels were evaluated: 1010, 5 x1010, 1011, 5 x1011, 1012 and 5 x1012 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 p27Kip1 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 high-risk PCa preceding RP. Preliminary evidence of biologic anti-tumor activity and systemic immune response was documented.