E.B. Butler

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

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.

Improvement in visual function in an eye with a presumed optic nerve sheath meningioma after treatment with three-dimensional conformal radiation therapy.

The treatment of optic nerve sheath meningiomas (ONSM) is controversial. Radiation therapy has been used with some success in patients with progressive visual loss. We report a case of visual improvement in a patient with an optic nerve sheath meningioma and progressive visual field loss, treated with conformal radiotherapy.

Suicide gene therapy for prostate cancer using a replication-deficient adenovirus containing the herpesvirus thymidine kinase gene.

Abstract Current therapies for localized prostate cancer include radical prostatectomy, local radiation therapy, and cryoablation and are associated with a high rate of cure and acceptable morbidity. However, for men who have failed primary curative attempts or have metastatic disease, no effective therapy associated with acceptable morbidity exists. “Suicide” gene therapy delivered alone or in combination with other forms of treatment could potentially provide simultaneous efficacy against localized and systemic disease via the generation of cytotoxic activity and/or systemic immunity to the cancer. In this article we discuss our preclinical and clinical experience with a herpes-simplex-virus thymidine kinase/ganciclovir gene-therapy protocol for prostate cancer.

Fractionated high-dose rate brachytherapy for intracranial gliomas.

PURPOSE To develop a catheter system for fractionated high-dose rate (HDR) brachytherapy for intracranial gliomas. METHODS AND MATERIALS The catheter system for stereotactic placement as well as delivery of the high-dose rate iridium-192 source wire is described. The force of the impulse wave from the source wire entering brain equivalent material was measured. Dose volume histograms for the first 5 patients treated are presented. RESULTS The catheter system was found to be satisfactory. The maximum force of the impulse wave was less than 1 acceleration of gravity (which is safe). The patients tolerated the treatment well with no significant problems related to the catheters being left in situ for up to 14 days. CONCLUSION Based on this pilot experience a phase I dose escalating and morbidity study has been initiated.

Pelvic radiotherapy does not increase the complication rates of artificial urinary sphincter implantation

Aims of Study Patients with pelvic radiotherapy (XRT) have impaired tissue healing capacity, small vessel occlusion and ischemia, and more complex etiology of incontinence secondary to detrusor hyperactivity and decreased compliance. It is unclear whether XRT increases the complication rates of artificial urinary sphincter (AUS) implantation for intrinsic sphincter deficiency (ISD) because of these adverse factors. Two recent publications revealed conflicting results (1, 2). We present the largest contemporary retrospective series to date to clarify the issue.