TY - JOUR
T1 - Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients
AU - Satoh, Takefumi
AU - Teh, Bin S.
AU - Timme, Terry L.
AU - Mai, Wei Yuan
AU - Gdor, Yehoshua
AU - Kusaka, Nobuyuki
AU - Fujita, Tetsuo
AU - Pramudji, Christina K.
AU - Vlachaki, Maria T.
AU - Ayala, Gustavo
AU - Wheeler, Thomas
AU - Amato, Robert
AU - Miles, Brian J.
AU - Kadmon, Dov
AU - Butler, Edward Brian
AU - Thompson, Timothy C.
N1 - Funding Information:
This work was supported by a specialized Program of Research Excellence (SPORE) grant (CA58204) from the National Cancer Institute, the Methodist Hospital Foundation, the General Clinical Research Center (GCRC). The authors thank Priscilla Miller and Anna Frolov for technical support.
Funding Information:
This work was supported by NIH SPORE Grant P50-58204.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/6/1
Y1 - 2004/6/1
N2 - 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.
AB - 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.
KW - Cytotoxic gene therapy
KW - HSV-tk/GCV gene therapy
KW - IMRT
KW - Prostate cancer
KW - Radio-gene therapy
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U2 - 10.1016/j.ijrobp.2004.01.020
DO - 10.1016/j.ijrobp.2004.01.020
M3 - Article
C2 - 15145177
AN - SCOPUS:2442512179
VL - 59
SP - 562
EP - 571
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
SN - 0360-3016
IS - 2
ER -