Concepts in Oncolytic Adenovirus Therapy

Abstract

Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.

Keywords: CRAd; adenovirus; arming; cancer; immunotherapy; oncolytic virus; tropism; vector design.

Figure 1

Structure of the wild-type adenovirus serotype 5 genome and the four concepts for generating conditionally replicating adenoviruses applied in vectors of current clinical trials. The affected E1 region is shown enlarged to illustrate the changes. The double-stranded DNA of about 36 kb in length (black horizontal arrows), flanked by two inverted terminal repeats (ITR) comprises four early transcription units (E1–E4, light grey boxes) and five late transcription units (L1–L5, dark grey boxes). The E1 region (enlarged below) consists of the encapsidation signal/E1A enhancer, the E1A promoter, E1A with four conserved regions (CR1–CR4) and E1B. The four concepts are listed below: Changes in the promoter (grey), Delta24 (blue) with a deletion in CR2, XVir-N-31 (purple) with a deletion in CR3, and ONYX-015 (green) with a stop codon and a deletion in E1B55K.

Figure 2

Mechanism of action of oncolytic adenoviruses in cancer cells. In normal, non-cancerous cells, oncolytic adenoviruses are unable to replicate upon infection leaving the cells unaffected. In tumour cells, the viruses can successfully replicate upon infection, leading to production of more virus progeny and eventual induction of immunogenic cell death (ICD). The cell lysis leads to release of virus progeny, pathogen-associated molecular patterns (PAMP), damage-associated molecular patterns (DAMP), and tumour associated antigens (TAA) into the tumour microenvironment (TME). The released virus progeny further infects the uninfected tumour cells and continues the viral spread. The immunostimulatory molecules released into the TME attract immune cells to the tumour and lead to the activation of both innate and adaptive immunity against the tumour (modified with permission from [52,54]).

Figure 3

Structure of the wild-type adenovirus serotype 5 genome and the concepts for altering natural tropism by fibre modification (upper section) and incorporating transgenes into the adenoviral E3 region (lower section). The affected L5 region encodes for the fibre protein; fibre monomer with tail, shaft, and knob domains is enlarged in the upper section to illustrate the modifications. Incorporation of an Arg-Gly-Asp motif (RGD) into the HI-loop enables attachment to the host cell via integrins, and C-terminal extension of lysin residues at the fibre head via heparansulfate-containing receptors. The lower section illustrates the two concepts of incorporating transgenes into the E3 region: (a) Most of the E3 region is retained while a transgene like the human granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adenoviral vector CG0070 is inserted, here GM-CSF expression is regulated by the E3 promoter. (b) Replacement of the E3 transcription unit with, for example, the pCMV-mOX40L-expression cassette in the adenoviral vector DNX-2440 where the expression of the mouse OX40L is regulated by the cytomegalovirus (CMV) promoter.