title: Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Satoh
authors.forename: Bin S
authors.initials: BS
authors.lastname: Teh
authors.forename: Terry L
authors.initials: TL
authors.lastname: Timme
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Mai
authors.forename: Yehoshua
authors.initials: Y
authors.lastname: Gdor
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kusaka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Fujita
authors.forename: Christina K
authors.initials: CK
authors.lastname: Pramudji
authors.forename: Maria T
authors.initials: MT
authors.lastname: Vlachaki
authors.forename: Gustavo
authors.initials: G
authors.lastname: Ayala
authors.forename: Thomas
authors.initials: T
authors.lastname: Wheeler
authors.forename: Robert
authors.initials: R
authors.lastname: Amato
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Miles
authors.forename: Dov
authors.initials: D
authors.lastname: Kadmon
authors.forename: E Brian
authors.initials: EB
authors.lastname: Butler
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use; D001358:Avian Sarcoma Viruses / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000627:therapeutic use; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D014633:Valine; D000077483:Valacyclovir; D015774:Ganciclovir; D000212:Acyclovir