Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer

Gustavo Ayala, Takefumi Satoh, Rile Li, Moshe Shalev, Yehoshua Gdor, Estuardo Aguilar-Cordova, Anna Frolov, Thomas M. Wheeler, Brian J. Miles, Katherine A Rauen, Bin S. Teh, Brian E. Butler, Timothy C. Thompson, Dov Kadmon

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.

Original languageEnglish (US)
Pages (from-to)716-728
Number of pages13
JournalMolecular Therapy
Volume13
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • Apoptosis
  • Car
  • Gene therapy
  • HSV-tk
  • Immune response
  • Microvessel density
  • Necrosis
  • Prostate cancer

ASJC Scopus subject areas

  • Molecular Biology

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  • Cite this

    Ayala, G., Satoh, T., Li, R., Shalev, M., Gdor, Y., Aguilar-Cordova, E., Frolov, A., Wheeler, T. M., Miles, B. J., Rauen, K. A., Teh, B. S., Butler, B. E., Thompson, T. C., & Kadmon, D. (2006). Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Molecular Therapy, 13(4), 716-728. https://doi.org/10.1016/j.ymthe.2005.11.022