Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications

Abstract

Adenoviruses (Ad) are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.

Keywords: adenovirus; cancer immunotherapy; chimeric vector; genetic masking; immune epitope; neutralization; oncolytic; pseudotyping; virotherapy.

Figure 1

Adenovirus particle with the three major antigenic capsid proteins. Penton base, hexon and fiber (shown here as monomers) are the main building blocks of the capsid structure, but also contain the major immunogenic epitopes (highlighted in colors) that are explained in greater detail in Section 1.3 of this review.

Figure 2

Top view of the Ad5 hexon monomer with the major antigenic epitopes. Hypervariable regions (HVRs) 1‒7 [33] shown in different colors; the site for point mutation (E451Q) central for ablation of human coagulation factor X (FX) binding [26] is shown in yellow; TET motif central for the high affinity interaction with coagulation factor VII (FVII) shown in orange [38]. The model was generated in PyMol version 1. 1eval (PDB ID: 3TG7).

Figure 3

Side and top view of the Ad5 fiber monomer. Main antigenic epitopes are highlighted in distinct colors (see legend) and hCAR-binding site is indicated in blue [43]. The model was generated in PyMol version 1.1eval (PDB ID: 1KNB). hCAR, human coxsackie and adenovirus receptor.

Figure 4

The Ad2 penton base monomer. The three main antigenic sites [57] are highlighted in blue, integrin-binding motif Arg-Gly-Asp (RGD) labelled in red [56,58]. The structure was constructed in PyMol version 1.1eval (PDB ID: 1X9P).

Figure 5

Global prevalence of neutralizing antibodies (nAbs). nAb titers against five different Ad viruses from subgroups C (Ad5, Ad6] and D (Ad26, Ad36] were determined from ~1900 individuals at 34 different locations in South America, Africa, Asia, Europe and United States. nd, not determined. Adapted from [12].