43. Long-Term T Cell Activation Following Combined In Situ Gene Therapy and Intensity-Modulated Radiotherapy Compared to Gene Therapy as Mono-Therapy in Prostate Cancer Patients.

Introduction: A program combining in situ gene therapy and intensity-modulated radiation therapy (IMRT) was implemented for the treatment of prostate cancer because the complementary mechanisms of cytotoxicity may have an enhanced efficacy. The in situ gene therapy comprised of adenoviral vector mediated Herpes Simplex Virus-thymidine kinase (AdHSVtk) + valacyclovir (VCV). We are currently conducting clinical trials using this approach. This study explores long-term immune responses following combined radio-gene therapy compared to gene therapy as mono-therapy.Methods: The study design included two separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in combination with IMRT for prostate cancer (31 patients) and Trial B gene therapy as mono-therapy for local recurrent prostate cancer after failing initial radiotherapy (36 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward until 12 months. Peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting (FACS) after the incubation with dual color labeled antibody pairs: CD45/CD14, CD3/CD19, CD3/CD8, CD3/CD4, CD8/HLA-DR, CD4/HLA-DR, CD3/HLA-DR, and CD3/CD56+CD16.Results: The pre-treatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 14.7% and 12.2% (Trials A and B, respectively). Two weeks after the vector injection, this increased to 31.7% and 21.9% (Trials A and B, respectively), and these increases were statistically significant (P < 0.0001 and P = 0.0188, respectively). Only in Trial A were significant increases seen at 4 weeks, 12 weeks, 4 months, 6 months, 8 months and 10 months (P < 0.0001, P = 0.0002, 0.0464, 0.0016, 0.0125 and 0.0354, respectively). In addition, activated CD4+ T cells were noted to increase significantly after the vector injection from 2 weeks till 12 months in Trial A only. (P = 0.0013 and 0.0069, respectively).Conclusions: This is the first report of long-term systemic immune responses following radio-gene therapy compared to gene therapy as mono-therapy. We present evidence showing long-term (up to 12 months) systemic T cell responses to two consecutive AdHSVtk injections during combination in situ gene therapy and IMRT for prostate cancer. These results suggest the potential for sustained activation of cell-mediated immune responses and may have enhanced activities against cancer. This combined approach may maximize tumor control, both local-regional and systemic through radio-gene therapy induced cytotoxicity and anti-tumor immunity.Molecular Therapy (2006) 13, S18–S18; doi: 10.1016/j.ymthe.2006.08.057 [ABSTRACT FROM AUTHOR]