Prostate-Specific Antigen Response and Systemic T Cell Activation After In Situ Gene Therapy in Prostate Cancer Patients Failing Radiotherapy

Abstract

In an extended phase I/II study we evaluated 36 prostate cancer patients with local recurrence after radiotherapy who received single or repeated cycles of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therapy with respect to serum PSA levels, alterations in immune cells, and numbers of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GCV gene therapy caused a significant prolongation of the mean serum PSA-doubling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the injected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It took a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) value. A repeated cycle of gene therapy failed to significantly extend PSADT but did result in significant increases in PSAR (29.4%) and TR-PSA (10.5 months). Moderately increased serum adenovirus antibody titers were generally observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T cells positive for the HLA-DR marker of activation in peripheral blood (p = 0.0088). Studies using prostate biopsies obtained at the same time point demonstrated that vector DNA was detectable by PCR in most samples yet all patients remained positive for prostate cancer in at least one biopsy core. Further analysis demonstrated a correlation between the level of CD8(+) cells and the number of apoptotic cells in biopsies containing cancer cells (p = 0.042). We conclude that repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to prostate cancer patients who failed radiotherapy and have a localized recurrence. Biological responses to this experimental therapy including increases in PSADT, PSAR, and TR-PSA, and activated CD8(+) T cells present in the peripheral blood, were demonstrated. Interestingly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.

Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model

“…Our previous studies using direct injection of adenoviral vectors that transduced the therapeutic HSV-tk therapeutic gene indicate that this procedure is safe and can be effectively accomplished. 35 Thus, the results of our studies suggest that an extension of this clinical protocol using IL-12-transduced DC or other gene-modified DC in a similar procedure should be pursued.…”

Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model

“…8 Initial studies with a direct cytotoxic approach, HSV-tk þ GCV, suggested that in situ gene therapy could generate an immune response in experimental systems. [9][10][11] Multiple clinical trials in men with this gene therapeutic approach have revealed necrosis within prostate cancer lesions in preference to adjacent normal prostatic tissues, 12 increased immune cells 12,13 and, when combined with radiation, an increase in the frequency of biopsies without evidence of cancer. 14 Additional studies have confirmed that intraprostatic adenoviral vector-mediated HSV-tk followed by systemic GCV treatment leads to increased numbers of HLA DR þ CD8 þ T cells in the peripheral blood of treated men.…”

“…14 Additional studies have confirmed that intraprostatic adenoviral vector-mediated HSV-tk followed by systemic GCV treatment leads to increased numbers of HLA DR þ CD8 þ T cells in the peripheral blood of treated men. 13,15 We have also tested another active vaccine approach involving the immunomodulatory gene IL-12. Preclinical studies with an adenoviral vector containing the IL-12 genes (AdIL-12) in an orthotopic mouse prostate cancer model indicate that this therapy suppresses not only local tumors and also lung metastases and generates systemic immune activities such as NK cells.…”

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

“…Several GDEPT combinations have been proposed (Springer and Niculescu-Duvaz, 1996), the most studied being the Herpes Simplex virus thymidine kinase/gancyclovir system (van Dillen et al, 2002). This combination has entered clinical trials, and shown safety and some efficacy (Sandmair et al, 2000;Miles et al, 2001).…”