Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients

Takefumi Satoh, Bin S. Teh, Terry L. Timme, Wei Yuan Mai, Yehoshua Gdor, Nobuyuki Kusaka, Tetsuo Fujita, Christina K. Pramudji, Maria T. Vlachaki, Gustavo Ayala, Thomas Wheeler, Robert Amato, Brian J. Miles, Dov Kadmon, Edward Brian Butler, Timothy C. Thompson

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Purpose In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or valacyclovir (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial. Methods and materials The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs. Results The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p < 0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035). Conclusions This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)562-571
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume59
Issue number2
DOIs
StatePublished - Jun 1 2004

Keywords

  • Cytotoxic gene therapy
  • HSV-tk/GCV gene therapy
  • IMRT
  • Prostate cancer
  • Radio-gene therapy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

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