Response of Retinoblastoma with Vitreous Seeds to Suicide Gene Therapy Using Adenoviral–mediated Delivery of Thymidine Kinase Followed by Ganciclovir

Abstract

Abstract: : Purpose: Vitreous seeds in patients with retinoblastoma are often resistant to standard therapies and frequently necessitate enucleation of eyes with useful vision. The purpose of this study was to determine the safety and assess the efficacy of using suicide gene therapy to treat retinoblastoma with vitreous seeds. Methods: An IBC, IRB, RAC and FDA approved pilot study utilizing intra–patient dose escalation was initiated to examine the feasibility of using an adenoviral vector containing a herpes thymidine kinase gene (AdV–TK) followed by systemic administration of ganciclovir to treat retinoblastoma. Patients had bilateral retinoblastoma with vitreous seeds refractory to standard therapies; enucleation of the remaining eye was imminent. Vitreous seeds were treated by intravitreous injection of AdV–TK adjacent to the site of disease. Each injection was followed by 7 days of ganciclovir delivered intravenously every 12 hours. Results: Eight patients with vitreous seeds have been enrolled. All patients have had a clinical response to treatment. The seven patients treated with doses ≥ 10¹⁰ viral particles (vp) had complete resolution of their vitreous seeds documented either by fundoscopy or histopathologic examination. Toxicity included mild inflammation at the 10¹⁰ vp dose and moderate inflammation, corneal edema, and increased intraocular pressure at the 10¹¹ vp dose. One patient is free of measurable retinoblastoma 27 months following therapy. There has been no evidence of extraocular spread of tumor along the needle tract in any patient. Conclusions: AdV–TK followed by ganciclovir can be safely administered to children with retinoblastoma. Patients with vitreous seeds appeared to respond. Suicide gene therapy may be able to contribute to the treatment of children with vitreous seeds as a complication of retinoblastoma.

Keywords: retinoblastoma • gene transfer/gene therapy • clinical (human) or epidemiologic studies: treatment/prevention assessment/controlled clinical trials