Oncolytic adenoviruses targeted to Human Papilloma Virus-positive head and neck squamous cell carcinomas

Abstract

Objectives In recent years, the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has markedly increased. Our aim was to design a novel therapeutic agent through the use of conditionally replicative adenoviruses (CRAds) that are targeted to the HPV E6 and E7 oncoproteins. Methods Each adenovirus included small deletion(s) in the E1a region of the genome (Δ24 or CB016) intended to allow for selective replication in HPV-positive cells. In vitro assays were performed to analyze the transduction efficiency of the vectors and the cell viability following viral infection. Then, the UPCI SCC 090 cell line (HPV-positive) was used to establish subcutaneous tumors in the flanks of nude mice. The tumors were then treated with either one dose of the virus or four doses (injected every fourth day). Results The transduction analysis with luciferase-expressing viruses demonstrated that the 5/3 fiber modification maximized virus infectivity. In vitro, both viruses (5/3Δ24 and 5/3CB016) demonstrated profound oncolytic effects. The 5/3CB016 virus was selective for only HPV-positive HNSCC cells, whereas the 5/3Δ24 virus killed HNSCC cells regardless of HPV status. In vivo, single injections of both viruses demonstrated anti-tumor effects until only 6–8 days following viral inoculation. However, after four viral injections, there was statistically significant reduction in tumor growth when compared to the control group (p<0.05). Conclusion CRAds targeted to HPV-positive HNSCCs demonstrated excellent in vitro and in vivo therapeutic effects, and they have the potential to be clinically translated as a novel treatment modality for this emerging disease.

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

“…Promoter-based CRAd Lung, prostate, ovarian, pancreatic cancer, adult T cell Leukemia/Lymphoma, glioma, meduloblastoma, sarcomas [69,[209][210][211][212][213][214][215][216][217][218][219][220][221][222] CRAds based on Interaction of essential viral genes withTumor-specific proteins colon, breast, non-small cell lung, head and neck, and pancreatic tumors, cervical carcinoma, glioblastoma, cancers with disturbed Rb pathway [172,[223][224][225][226][227][228] As with genes, several endogenous miRNAs and other lncRNAs can be targeted to enhance the detargeting and retargeting ability of OAdVs [229]. For instance, liver, where most of the OAdV sequestration is observed, overexpresses miRNA122 and miR145.…”

Oncolytic Adenovirus Harboring Interleukin-24 Improves Chemotherapy for Advanced Prostate Cancer

“…However, currently the administration of oncolytic virus is limited to intratumoral injection, because intravenous administration is easy to produce antibodies against the virus. Therefore, clinical trials of oncolytic viruses are limited to superficial tumors such as head and neck cancer 15 . Due to special anatomical structure of the prostate, viral particle can be accurately injected into prostate cancer lesions guided by ultrasound in phase I clinical trials 16 , 17 .…”

Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials

“…One example in many cancers is a defect in the Retinoblastoma (RB)-E2F pathway, which ultimately allows a virus to replicate as its normally negative regulatory function is absent [ 16 ]. Also, regulatory proteins from certain cancers (such as the human papilloma virus E6 and E7 oncoproteins) can functionally transcomplement missing viral proteins (such those in an adenovirus with E1 deletions) to allow for viral replication [ 21 , 22 ]. No matter the mechanism, a key component of any well-designed vector is the ability to selectively replicate in target cells of interest.…”