Oncolytic Adenovirus-A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, particularly in China. Despite the development of HCC treatment strategies, the survival rate remains unpleasant. Gene-targeted oncolytic viral therapy (GTOVT) is an emerging treatment modality-a kind of cancer-targeted therapy-which creates viral vectors armed with anti-cancer genes. The adenovirus is a promising agent for GAOVT due to its many advantages. In spite of the oncolytic adenovirus itself, the host immune response is the determining factor for the anti-cancer efficacy. In this review, we have summarized recent developments in oncolytic adenovirus engineering and the development of novel therapeutic genes utilized in HCC treatment. Furthermore, the diversified roles the immune response plays in oncolytic adenovirus therapy and recent attempts to modulate immune responses to enhance the anti-cancer efficacy of oncolytic adenovirus have been discussed.

Keywords: HCC; adenovirus; gene-targeted oncolytic viral therapy; immunotherapy; virus engineering.

Figure 1

The scheme of the wild type serotype 5 adenovirus genome. The genome consists of four early transcription elements (E1, E2, E3, and E4) and five late expression genes (L1–L5) associated with adenoviral particle assembly. The E1 gene is required for the activation of the transcription of early genes; the E2 gene is required for virus DNA replication; the E3 gene is required for the modulation and evasion of the host's immune response, prevention of untimely cell death through apoptosis, and efficient cell lysis once new particle assembly is complete; the E4 gene is involved in virus RNA metabolism and transport, preferential downregulation of host-cell protein synthesis, and enhancement of virus DNA replication. The deletion of both the E1 and E3 genes can accommodate up to 7.5 kb of foreign DNA and is commonly used in gene therapy. E4 gene deletion further reduces induction of vector-specific immune responses and minimizes the outgrowth of replication-competent viruses in packaging cell lines.

Figure 2

Diagram of oncolytic adenovirus infection. Oncolytic adenovirus infections initiated by fiber knob interact with the primary receptor on the cell membrane. Primary receptors are different according to adenovirus serotype. Afterwards, the penton base directly binds to secondary receptors that complete virus infection.

Figure 3

The genetic modifications of common oncolytic adenovirus vectors. (A) The genetic scheme of wild type serotype 5 adenovirus. (B) ONYX-015, the E1b-55k (2496-3323) region that is capable of replication in p53-deficient human tumor cells was deleted. (C) H101, deleting the entire E1B gene and a 78.3–85.8 nm gene segment in the E3 region, which is responsible for the code of the adenovirus death protein. (D) Ad5-Δ24RGD carries a 24-bp (919–943) deletion in the E1A region that is responsible for binding Rb protein and RGD motif insertion into the fiber. (E) ZD55 deleted the E1B 55-kD gene and armed with foreign gene. (F) ICOVIR5, the oncolytic adenovirus in which the endogenous E1A promoter has been replaced by the human E2F-1 promoter insulated with the DM-1. (G) Gendicine is a recombinant human serotype 5 adenovirus in which the E1 region is replaced by a human wild-type p53 expression cassette. Gendicine is a recombinant human serotype 5 adenovirus in which the E1 region is replaced by a human wild-type p53 expression cassette. The p53 gene is driven by a Rous sarcoma virus (RSV) promoter with a bovine growth hormone (BGH) poly(A) tail.