Oncolytic adenoviral replication-permissive cell sheet as a local delivery platform for the treatment of multifocal hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is highly aggressive and malignant. One of the key attributes of HCC is its multifocality, which contributes to its aggressiveness and high recurrence rate, ultimately resulting in poor disease management with conventional cancer therapies. In this regard, oncolytic adenovirus (Ad), which selectively replicates in cancer cells and shows hepatic tropism, could be a promising alternative to treat multifocal HCC with minimal off-target side effects. However, short half-life and high-level immunogenicity of systemically administered Ad remains a critical safety concern. To address these limitations, cancer cell and fibroblast layered cell sheets (CFCS) was explored as a local delivery platform, which is biodegradable and permissive toward replication of oncolytic Ad, was used to cover large areas of HCC-harboring livers and deliver decorin (DCN) expressing oncolytic Ad (oAd-DCN/CFCSs). CFCSs allowed effective replication of oAd-DCN and expression of therapeutic genes in vitro. Furthermore, CFCSs enabled prolonged retainment of oAd-DCN in tumor tissues by enabling active replication of virions both in CFCS and tumor tissues until CFCSs was completely degraded in 1-week period. This has allowed oAd-DCN/CFCSs to elicit more potent antitumor effect and effectively prevented formation of multifocal HCCs than systemically or locally administered oAd-DCN. Further, CFCS-mediated delivery of oAd-DCN prevented nonspecific shedding of virions from the tumor sites to adjacent and distant normal tissues. Collectively, these findings show that single administration of the oncolytic Ad loaded in CFCSs may prolong, amplify, and potentiate the therapeutic efficacy of Ad as well as enhancing its safety profile by simultaneously enhancing intratumoral localization and preventing nonspecific shedding of the virus.