Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.
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.
Satoh
Takefumi
T
Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Teh
Bin S
BS
Timme
Terry L
TL
Mai
Wei-Yuan
WY
Gdor
Yehoshua
Y
Kusaka
Nobuyuki
N
Fujita
Tetsuo
T
Pramudji
Christina K
CK
Vlachaki
Maria T
MT
Ayala
Gustavo
G
Wheeler
Thomas
T
Amato
Robert
R
Miles
Brian J
BJ
Kadmon
Dov
D
Butler
E Brian
EB
Thompson
Timothy C
TC
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
D000998:Antiviral Agents; D011355:Prodrugs; D013937:Thymidine Kinase; D014633:Valine; D000077483:Valacyclovir; D015774:Ganciclovir; D000212:Acyclovir