Demonstration of a rational strategy for human prostate cancer gene therapy

M. G. Sanda, S. R. Ayyagari, Elizabeth Jaffee, Jonathan Ira Epstein, S. L. Clift, L. K. Cohen, G. Dranoff, Andrew Mark Pardoll, R. C. Mulligan, J. W. Simons

Research output: Contribution to journalArticle

Abstract

The potential efficacy and clinical feasibility of gene therapy for prostate cancer were tested. Efficacy was tested using the Dunning rat prostate carcinoma model. Rats with anaplastic, hormone refractory prostate cancer treated with irradiated prostate cancer cells genetically engineered to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF) showed longer disease-free survival compared to either untreated control rats or rats receiving prostate cancer cell vaccine mixed with soluble human GM- CSF. A gene modified prostate cancer cell vaccine thus provided effective therapy for anaplastic, hormone refractory prostate cancer in this animal model. An evaluation of the clinical feasibility of gene therapy for human prostate cancer based on these findings was then undertaken. Prostate cancer cells from patients with stage T2 prostate cancer undergoing radical prostatectomy were first transduced with MFG-lacZ, a retroviral vector carrying the β-galactosidase reporter gene. Efficient gene transfer was achieved in each of 16 consecutive cases (median transduction efficiency 35%, range 12 to 65%). Cotransduction with a drug-selectable gene was not required to achieve high yield of genetically modified cells. Histopathology confirmed malignant origin of these cells and immunofluorescence analysis of cytokeratin 18 expression confirmed prostatic luminal-epithelial phenotype in each case tested. Cell yields (2.5 x 108 cells per gram of prostate cancer) were sufficient for potential entry into clinical trials. Autologous human prostate cancer vaccine cells were then transduced with MFG-GM-CSF, and significant human GM-CSF secretion was achieved in each of 10 consecutive cases. Sequential transductions increased GM-CSF secretion in each of 3 cases tested, demonstrating that increased gene dose can be used to escalate desired gene expression in individual patients. These studies show a preclinical basis for proceeding with clinical trials of gene therapy for human prostate cancer.

Original languageEnglish (US)
Pages (from-to)622-628
Number of pages7
JournalJournal of Urology
Volume151
Issue number3
StatePublished - 1994

Fingerprint

Neoplasm Genes
Genetic Therapy
Prostatic Neoplasms
Granulocyte-Macrophage Colony-Stimulating Factor
Cancer Vaccines
Genes
Clinical Trials
Galactosidases
Hormones
Keratin-18
Prostatectomy
Reporter Genes
Disease-Free Survival
Fluorescent Antibody Technique
Prostate
Animal Models

Keywords

  • gene therapy
  • granulocyte-macrophage colony-stimulating factor
  • immunotherapy
  • prostatic neoplasms

ASJC Scopus subject areas

  • Urology

Cite this

Sanda, M. G., Ayyagari, S. R., Jaffee, E., Epstein, J. I., Clift, S. L., Cohen, L. K., ... Simons, J. W. (1994). Demonstration of a rational strategy for human prostate cancer gene therapy. Journal of Urology, 151(3), 622-628.

Demonstration of a rational strategy for human prostate cancer gene therapy. / Sanda, M. G.; Ayyagari, S. R.; Jaffee, Elizabeth; Epstein, Jonathan Ira; Clift, S. L.; Cohen, L. K.; Dranoff, G.; Pardoll, Andrew Mark; Mulligan, R. C.; Simons, J. W.

In: Journal of Urology, Vol. 151, No. 3, 1994, p. 622-628.

Research output: Contribution to journalArticle

Sanda, MG, Ayyagari, SR, Jaffee, E, Epstein, JI, Clift, SL, Cohen, LK, Dranoff, G, Pardoll, AM, Mulligan, RC & Simons, JW 1994, 'Demonstration of a rational strategy for human prostate cancer gene therapy', Journal of Urology, vol. 151, no. 3, pp. 622-628.
Sanda, M. G. ; Ayyagari, S. R. ; Jaffee, Elizabeth ; Epstein, Jonathan Ira ; Clift, S. L. ; Cohen, L. K. ; Dranoff, G. ; Pardoll, Andrew Mark ; Mulligan, R. C. ; Simons, J. W. / Demonstration of a rational strategy for human prostate cancer gene therapy. In: Journal of Urology. 1994 ; Vol. 151, No. 3. pp. 622-628.
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