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

Abstract

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressorRB1. 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.

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. “Alive, with good vision and no comorbidity”

“…Other viral vectors for retinoblastoma gene therapy induce an oncolytic effect, such as the adenoviruses H101 (Song et al, 2010) and Ad-TERT p-E1 (Wang et al, 2013), which have been tested in preclinical studies. Currently, the most advanced oncolytic adenovirus for retinoblastoma is VCN-01, designed to replicate selectively in tumor cells with high abundance of free E2F-1 transcription factor activity due to the dysfunctional RB1 pathway (Pascual-Pasto et al, 2019). The genome of VCN-01 contains one deletion in the E1A gene that precludes viral replication in RB1-functional cells and one insertion of an E2F1 promoter under the E1A gene that favors replication in cells with free E2F-1 (Rodriguez-Garcia et al, 2015).…”

Delivery and Biosafety of Oncolytic Virotherapy

“…Warner et al demonstrated that early expression of hNIS in colon cancer cells made viral replication reliably imageable via positron emission tomography (PET) of I-124 uptake (45). Direct intratumoral injection of oncolytic adenovirus VCN-01 for the treatment of retinoblastoma has also been shown to be effective (46). Choi et al proved that CF33 (a novel chimeric orthopoxvirus encoding luciferase, enabling real-time view of cell infection), was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in triple-negative breast cancer (TNBC, an aggressive subtype of breast cancer with high recurrence rate and poor prognosis) lines with PI3K/AKT pathway mutations (47).…”

“…Thus, blindly increasing the application concentration of the virus to compensate for its lack of selectivity will inevitably increase the public concern about the safety of oncolytic virotherapy. Requires highly selective tissue targets (55) Absorbed slower than intravenous injection (65) Limited to central nervous system tumors (68) Applied only to small animals in which veins are difficult to find (65) Complex procedures make repeat dosing difficult (61,63) Physiological barriers such as blood-brain barrier and oncolytic virus elimination by the immune system (55) Mostly applied in vitro experiments (39,42,(44)(45)(46)(47) This route of administration, if any, would be the most likely to lead to toxicity (65) Additionally, those considering use of intravenous administration of an oncolytic virus also need to consider the existence of physiological barriers, such as blood-brain barrier, and the elimination of oncolytic virus by the immune system (55). Is it possible that a wide variety of oncolytic viruses can bypass the blood-brain barrier?…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…VCN-01 is an OAd expressing PH20 hyaluronidase [155], PH20 hyaluronidase can promote the spread of OVs between tumor cells by degrading the ECM. VCN-01 has now entered clinical trials for the treatment of pancreatic adenocarcinoma and retinoblastoma [156].…”