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Heterogeneous delivery is a barrier to the translational advancement of oncolytic virotherapy for treating solid tumors

Authors Miller AC, Russell SJ

Received 9 April 2014

Accepted for publication 29 April 2014

Published 29 July 2014 Volume 2014:6 Pages 11—31

DOI https://doi.org/10.2147/VAAT.S50110

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Amber C Miller,1,2 Stephen J Russell2,3

1Mayo Graduate School, Mayo Clinic, Rochester, Minnesota, USA; 2Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; 3Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA

Abstract: Oncolytic viruses are a promising experimental anticancer therapy currently undergoing clinical translation. The development of oncolytic virotherapy offers a potential solution to the elusive “one-shot”cancer cure by providing targeted therapy to selectively infect and kill cancer cells while provoking adaptive anticancer immune responses as protection against distant metastasis and recurrent tumor challenge. While this technology has overcome barriers to safety and efficacy through cancer-specific targeting techniques, in order to reach full therapeutic potential, oncolytic therapies must still overcome barriers to intratumoral delivery and spread that result in heterogeneous intratumoral delivery and nonuniform response. This review will discuss barriers to oncolytic virotherapy translation related to mechanisms of delivering virus via tumor vasculature and distributing virus throughout the tumor microenvironment. Barriers include extravasation into the tumor that is dependent on adequate blood flow, tissue perfusion, and tumoral enhanced permeability and retention for transvascular transport. Subsequently, virions must undergo interstitial transport against dense stromal barriers and high interstitial fluid pressure to initiate infection. In order to achieve massive tumor regression, infection must spread to cover large volumes of tumor mass. Furthermore, virus bioavailability is quickly dampened upon systemic administration due to neutralization and sequestration. These barriers to delivery limit the amount of virus that effectively reaches and spreads within the tumor, forcing dose increases that impinge upon limits of production and increase possibility of adverse events. Techniques to overcome these barriers are discussed but largely remain to be translated into clinical use.

Keywords: oncolytic virotherapy, barriers, delivery, systemic therapy, translation

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