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P. Chevez–Barrios, A. Leen, S.J. Chai, M. Chintagumpala, W.F. Mieler, E. Paysse, K. Wilhelmus, M.Y. Hurwitz, C. Rooney, R.L. Hurwitz; Immune Response of Retinoblastoma Treated With Suicide Gene Therapy Using Adenoviral–Mediated Delivery of Thymidine Kinase Followed by Ganciclovir . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5218.
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Purpose: The contribution of anti–tumor response to the efficacy of suicide gene therapy for retinoblastoma is unclear. The purpose of this study was to evaluate potential local and systemic immune responses to the adenoviral vector used for treatment of patients with vitreous tumor seeding. Methods: An IBC, IRB, RAC and FDA approved pilot study of intra–patient dose escalation was initiated to examine the feasibility of using intravitreal injections of an adenoviral vector containing a herpes thymidine kinase gene (AdV–TK) followed by systemic administration of ganciclovir to treat retinoblastoma. Blood samples were drawn weekly before and after the intraocular injections and the T cells were examined for evidence of adenovirus–specific reactivity. For patients who required enucleation, histologic and immunohistochemical examination of the eyes was performed to identify the cellular inflammatory component. Results: 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. No patient had an increase in antibody titer to adenovirus following therapy. Blood samples of four patients were studied and no significant changes in the precursor frequency of adenovirus–specific T cells in peripheral blood were documented. The majority of the treated eyes positively stained with the plasma cell marker CD138, and the T–cell markers CD3, CD5 and CD43 especially in the uveal tract, retina and vitreous. The T–cell marker TdT was negative in all cases. CD68 macrophagic cells were seen in the retina and vitreous. The B–cell marker L26 was only positive in a child without evidence of disease at time of enucleation. Conclusions: The intraocular inflammatory response is composed mainly of plasma cells, histiocytes and CD3, CD5 and CD43 T cells. Preliminary results suggest that AdV–TK followed by ganciclovir administered to children with retinoblastoma does not induce or boost systemic immunity to adenovirus.
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