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: Guru Sonpavde, Timothy C Thompson, Rajul K Jain, Gustavo E Ayala, Shinji Kurosaka, Kohei Edamura, Ken-ichi Tabata, Chengzhen Ren, Alexei A Goltsov, Martha P Mims, Teresa G Hayes, Michael M Ittmann, Thomas M Wheeler, Adrian Gee, Brian J Miles, Dov Kadmon
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 22 Pg. 7174-82 (Nov 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21933889 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• GLIPR1 protein, human
• Membrane Proteins
• Neoplasm Proteins
• Nerve Tissue Proteins

Topics

• Adenoviridae (genetics)
• Aged
• Gene Transfer Techniques
• Genes, Suppressor
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Male
• Membrane Proteins
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Proteins (genetics)
• Nerve Tissue Proteins (genetics)
• Prostatectomy
• Prostatic Neoplasms (pathology, surgery, therapy)
• Risk