TY - JOUR
T1 - GLIPR1 tumor suppressor gene expressed by adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy
AU - Sonpavde, Guru
AU - Thompson, Timothy C.
AU - Jain, Rajul K.
AU - Ayala, Gustavo E.
AU - Kurosaka, Shinji
AU - Edamura, Kohei
AU - Tabata, Ken Ichi
AU - Ren, Chengzhen
AU - Goltsov, Alexei A.
AU - Mims, Martha P.
AU - Hayes, Teresa G.
AU - Ittmann, Michael M.
AU - Wheeler, Thomas M.
AU - Gee, Adrian
AU - Miles, Brian J.
AU - Kadmon, Dov
PY - 2011/11/15
Y1 - 2011/11/15
N2 - 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 Kip1upregulation 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.
AB - 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 Kip1upregulation 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.
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U2 - 10.1158/1078-0432.CCR-11-1899
DO - 10.1158/1078-0432.CCR-11-1899
M3 - Article
C2 - 21933889
AN - SCOPUS:81255143331
SN - 1078-0432
VL - 17
SP - 7174
EP - 7182
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -