Directing systemic oncolytic viral delivery to tumors via carrier cells

Abstract

The systemic administration of oncolytic virus (OV) is often inefficient due to clearance of the virus by host defense mechanism and spurious targeting of non-cancer tissues through the bloodstream. Cell mediated OV delivery could hide the virus from host defenses and direct them toward tumors: Mesenchymal and neural stem cells have been described to possess tumor-homing ability as well as the capacity to deliver OVs. In this review, we will focus on approaches where OV and carrier cells are utilized for cancer therapy. Effective cellular internalization and replication of OVs need to occur both in cancer and carrier cells. We thus will discuss the current challenges faced by the use of OV delivery via carrier cells.

Fig. 1

Schematic overviews of the carrier cell-based oncolytic virus (OV) delivery to tumors. Cellular tropism (purple shaded region): Cellular internalization of Adenovirus serotype 5 (Ad5) and herpes simplex viruses type 1 (HSV-1) depends on cellular receptor expressions: Coxsackie and Adenovirus Receptor (CAR) for Ad5 fiber and nectin-1, 2, HVEM and several 3-O-sulphotransferase-modified heparan sulphates for HSV-1 gD . Cellular retargeting is achieved by viral ligand modifications by means of covalent linkage to peptides that can target cellular receptors, by using chimeras with other adenoviral serotype proteins or by using single-chain antibodies (scFv) to link adenoviral entry to a specific cellular receptor. Conditional replication (green shaded region): Ad5 E1A mutation and transcriptional regulation by tissue-specific promoter (e.g. CXCR4) achieve conditional viral replication. Tumor-specific HSV-1 replication is based on the deletions of UL39 gene (ICP6) and/or γ34.5 genes (ICP34.5), and conditional γ34.5 gene transcription by tumor-specific promoters (e.g. nestin). Carrier cells (blue shaded region): mesenchymal/neural stem cells (MSC, NSC), immune cells (T cells), or cancer cells themselves have been used as carrier cells to deliver Ovs, usually through intravascular (intravenous and carotid artery) or local (e.g. intracranial) administration. Carrier cells can migrate to tumor beds attracted by chemotactic mediators secreted from the tumor microenvironment. Carrier cells allow OV replication to release progeny OVs toward tumors.