Research ArticleCancer

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01

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Science Translational Medicine  23 Jan 2019:
Vol. 11, Issue 476, eaat9321
DOI: 10.1126/scitranslmed.aat9321

An oncolytic virus to blast retinoblastoma

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.

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