604. Phase I/II Clinical Trial of Ad-OC-TK plus VAL for the Patients with Metastatic or Local Recurrent Prostate Cancer: Initial Experience in Japan

Abstract

Top of pageAbstract Background: The absence of effective therapies for hormone refractory prostate cancer establishes the need to develop novel therapeutic modality, such as a gene therapy, that can be applied either separately or in conjunction with current treatment modalities for the treatment of advanced prostate cancer. Previously, Gardner and Chung have conducted the phase I clinical trial of the Ad-OC-TK (recombinant adenoviral vector containing osteocalcin promoter driven herpes-simplex-virus thymidine kinase gene) plus VAL (Valacyclovior) for the treatment of hormone-refractory prostate cancer at the University of Virginia. Our progress report of the ongoing phase I/II clinical trial of Ad-OC-TK plus VAL for the advanced prostate cancer at the Kobe University Hospital, Japan will be presented. Methods: To date, two patients with localized recurrence or bone metastasis of hormone refractory prostate cancer were enrolled. A dose of Ad-OC-TK injected directly to localized recurrent tumor or bone metastatic lesion was 2.5 × 109 plaque-forming unit (PFU) / Day 1 and Day 8. Patient was given one gram of VAL twice daily for 21 days. Blood, urine and tissue specimens were obtained and were subjected to the evaluation for virus titers, PCR analysis for the distribution of hsvTK gene, and bioassay of the virus. Immunohistochemical studies were performed to observe the expression of OC, Coxackie Adenovirus Receptor (CAR), hsvTK enzyme, and apoptotic cells in the biopsy specimens from treated lesions. Quantitative analysis of bone scintigraphy was performed to characterize the response of the patient with bone metastasis. Results: The initial patients tolerated this therapy without serious adverse events. Despite intralesional injections, both the hsvTK and adenoviral genes were able to detect in peripheral blood samples. Biopsies of each lesion demonstrated hsvTK, CAR and OC proteins after treatment demonstrating transcriptional expression in these specimens and increased apoptosis post-treatment observed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay. Initially, serum PSA levels declined in both patients coincident with valacyclovir pro-drug activation of hsv-TK. The quantitative analysis of bone scintigraphy showed the decreased RI accumulation only in injected lesion. Conclusion: The Ad-OC-TK plus VAL therapy as a tissue-specific OC promoter-based toxic gene therapy has demonstrated the localized anti-tumor effect without any serious adverse events in the initial Japanese patients with hormone-refractory prostate cancer.