RT Journal Article
SR Electronic
T1 Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaat9321
DO 10.1126/scitranslmed.aat9321
VO 11
IS 476
A1 Pascual-Pasto, Guillem
A1 Bazan-Peregrino, Miriam
A1 Olaciregui, Nagore G.
A1 Restrepo-Perdomo, Camilo A.
A1 Mato-Berciano, Ana
A1 Ottaviani, Daniela
A1 Weber, Klaus
A1 Correa, Genoveva
A1 Paco, Sonia
A1 Vila-Ubach, Monica
A1 Cuadrado-Vilanova, Maria
A1 Castillo-Ecija, Helena
A1 Botteri, Gaia
A1 Garcia-Gerique, Laura
A1 Moreno-Gilabert, Helena
A1 Gimenez-Alejandre, Marta
A1 Alonso-Lopez, Patricia
A1 Farrera-Sal, Marti
A1 Torres-Manjon, Silvia
A1 Ramos-Lozano, Dolores
A1 Moreno, Rafael
A1 Aerts, Isabelle
A1 Doz, François
A1 Cassoux, Nathalie
A1 Chapeaublanc, Elodie
A1 Torrebadell, Montserrat
A1 Roldan, Monica
A1 König, Andrés
A1 Suñol, Mariona
A1 Claverol, Joana
A1 Lavarino, Cinzia
A1 Carmen de, Torres
A1 Fu, Ligia
A1 Radvanyi, François
A1 Munier, Francis L.
A1 Catalá-Mora, Jaume
A1 Mora, Jaume
A1 Alemany, Ramón
A1 Cascalló, Manel
A1 Chantada, Guillermo L.
A1 Carcaboso, Angel M.
YR 2019
UL http://stm.sciencemag.org/content/11/476/eaat9321.abstract
AB Eyes afflicted by chemoresistant retinoblastoma may need to be surgically removed to prevent life-threatening metastasis. To develop alternative treatments for retinoblastoma, Pascual-Pasto et al. investigated the oncolytic adenovirus VCN-01, which targets cells with dysregulated RB1. They found that VCN-01 can lyse even chemoresistant patient samples in vitro and was effective in mouse xenograft models. VCN-01 was safe in mice and juvenile rabbits. Initial results from the first pediatric retinoblastoma patients treated with intravitreous VCN-01 showed viral replication in tumor cells and no systemic inflammation. These encouraging results support the development of this oncolytic virus to be used for retinoblastoma therapy.Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1. VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.