Virotherapy of Ovarian Cancer With Polymer-cloaked Adenovirus Retargeted to the Epidermal Growth Factor Receptor

Abstract

Adenovirus gene therapy for intraperitoneal (IP) cancer is limited in clinical trials by inefficient tumor cell transduction and development of peritoneal adhesions. We have shown previously that normal virus tropism can be ablated by physically shielding the virus surface with reactive hydrophilic polymers and that linkage of novel ligands enables virus "retargeting" through chosen receptors. To achieve tumor-selective infection, polymer-coated virus was retargeted using murine epidermal growth factor (mEGF). The resulting mEGF-polymer coated adenovirus lost its normal broad tropism and transduced cells selectively via the EGF receptor (EGFR). We assessed whether this approach could be used to target lytic "virotherapy" using wild-type adenovirus (Ad5WT) in a peritoneal xenograft model of human ovarian cancer. Oncolytic activity of Ad5WT was retained following polymer coating and mEGF-retargeting. Importantly, adhesion formation was markedly decreased compared with the unmodified virus, and no dose-limiting toxicities were observed following treatment with mEGF-retargeted polymer-coated virus. Restricting virus tropism by physical coating, coupled with tumor-selective retargeting promises to combine good anticancer efficacy with acceptable toxicity, enabling application of elevated virus doses leading to an improved therapeutic outcome.

Gene-Directed Enzyme Prodrug Cancer Therapy

“…In order to redirect the tropism of viruses to specifically target tumor cells, some attempts have been made to change the mechanism of virus internalization and create a "retargeted transduction" viral vector [114]. For example, Morrison et al used a hydrophilic polymer, N-(2-hydroxypropyl) methacrylamide (HPMA), to shield the viral capsid, followed by "recoating" of the virus by chemical conjugation of the murine epidermal growth factor [115]. The new virus lost its infectious ability via CAR and was able to target an EGFR-expressing ovarian tumor cell line [115].…”

Current advances in adenovirus nanocomplexes: more specificity and less immunogenicity

“…2.1). The outer shell or distal end of PEG in Ad/polymer complexes has been conjugated with active targeting moieties such as antibodies (22), growth factors (31,(33)(34)(35)(36)(37)(38)(39), small molecular complexes of peptides (arginineglycine-aspartic acid; RGD), and ligands (27,40) in order to direct Ad to a targeted disease site (41). Direction of Ad complexes via affinity tags results in accumulation of a high concentration of Ad nanocomplexes in tumor sites, leading to highly effective gene expression.…”

Targeting glioblastoma with oncolytic adenovirus delta 24

“…Thus, genetic engineering has been used to modify viral genome in order to produce molecules toxic for cancer cells, in order to increase the cytopathic effect. [10] Furthermore, genes have been employed, causing an augmented immune response against virally infected cells, [11] meanwhile other strategies involve the modulation of vessel permeability for viruses [8] and degradation of extracellular matrix. [12] DEVELOPMENT OF ONCOLYTIC ADENOVIRUS DELTA 24…”