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

Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):562-71. doi: 10.1016/j.ijrobp.2004.01.020.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyclovir / analogs & derivatives*
  • Acyclovir / therapeutic use
  • Adenoviridae / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / therapeutic use
  • Avian Sarcoma Viruses / genetics
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Combined Modality Therapy
  • Ganciclovir / therapeutic use
  • Genetic Therapy*
  • Humans
  • Lymphocyte Activation / immunology*
  • Male
  • Middle Aged
  • Prodrugs / therapeutic use
  • Prostatectomy
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / radiotherapy
  • Prostatic Neoplasms / therapy*
  • Thymidine Kinase / genetics*
  • Valacyclovir
  • Valine / analogs & derivatives*
  • Valine / therapeutic use


  • Antiviral Agents
  • Prodrugs
  • Thymidine Kinase
  • Valine
  • Valacyclovir
  • Ganciclovir
  • Acyclovir