Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir.
OBJECTIVE
To evaluate the feasibility and safety of adenovirus-mediated gene therapy as a treatment for tumor seeds in the vitreous of children with retinoblastoma.


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 10(8) viral particles (vp) had resolution of the tumor seeds around the injection site. The seven patients who were treated with doses > or = 10(10) vp had resolution of their vitreous tumor seeds documented by fundoscopy. Toxicity included mild inflammation at 10(10) vp and moderate inflammation, corneal edema, and increased intraocular pressure at 10(11) 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.


CONCLUSIONS
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.
Chévez-Barrios
Patricia
P
Department of Pathology, Texas Children's Cancer Center, Houston, USA.
Chintagumpala
Murali
M
Mieler
William
W
Paysse
Evelyn
E
Boniuk
Milton
M
Kozinetz
Claudia
C
Hurwitz
Mary Y
MY
Hurwitz
Richard L
RL
D000260:Adenoviruses, Human / Q000235:genetics*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002648:Child; D003131:Combined Modality Therapy; D005240:Feasibility Studies; D015774:Ganciclovir / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D009366:Neoplasm Seeding; D019572:Retinal Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D012175:Retinoblastoma / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics / Q000627:therapeutic use*; D014822:Vitreous Body / Q000187:drug effects / Q000473:pathology*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir