Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir

Purpose: To evaluate the feasibility and safety of adenovirus-mediated gene therapy as a treatment for tumor seeds in the vitreous of children with retinoblastoma. Patients and Methods: An Institutional Biosafety Committee-, Institutional Review Board-, Recombinant DNA Advisory Committee-, and US Food and Drug Administration-approved phase I study used intrapatient dose escalation of adenoviral vector containing a herpes simplex thymidine kinase gene (AdV-TK) followed by systemic administration of ganciclovir to treat bilateral retinoblastoma with vitreous tumor seeding refractory to standard therapies. Vitreous tumor seeds were treated by intravitreous injection of AdV-TK adjacent to disease sites. Each injection was followed by ganciclovir delivered intravenously every 12 hours for 7 days. Results: Eight patients with vitreous tumor seeds were enrolled. One patient who was treated with 10⁸ viral particles (vp) had resolution of the tumor seeds around the injection site. The seven patients who were treated with doses ≥ 10¹⁰ vp had resolution of their vitreous tumor seeds documented by fundoscopy. Toxicity included mild inflammation at 10¹⁰ vp and moderate inflammation, corneal edema, and increased intraocular pressure at 10¹¹ vp. One patient was free of active vitreous tumor seeds 38 months after therapy. There has been no evidence of extraocular spread of tumor along the needle tract in any patient. Conclusion: AdV-TK followed by ganciclovir can be administered safely to children with retinoblastoma. Suicide gene therapy may contribute to the treatment of children with retinoblastoma tumor seeds in the vitreous, a resistant complication of retinoblastoma.