Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy

Abstract

Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.

Keywords: adenoviral vectors; adenovirus; adenovirus library; cancer; chemotherapy; delivery; immunotherapy; oncolytic adenovirus; radiotherapy.

Figure 1

Strategies to overcome potential barriers in delivering oncolytic adenoviruses (OAs) into tumor sites. For systemic administration (a) such as intravenous injection, the complement, neutralizing antibodies, platelets and erythrocytes present in blood circulation bind to OAs (b) and block the migration of OAs into tumor sites. Cell carriers and extracellular-vesicles-delivered OAs escape the above-mentioned barriers to some extent before the OAs reach the tumor site (c). Local infusion represents an alternative strategy to avoid the interaction with blood components (d).

Figure 2

Oncolytic adenoviruses (OAs) in the tumor microenvironment. The OAs inhibit cancer growth through direct killing of cancer cells (green) and the stimulation of immunity in the tumor microenvironment. OAs replicate in and kill cancer cells, resulting cell debris, which are engulfed by macrophages (grey). Macrophages process cell debris-derived antigens and present them to T cells (blue). T cells are then activated and release cytokines, which induce apoptosis or necrosis of cancer cells.

Figure 3

Cloned adenoviruses and modifications. (a) List of cloned wild-type adenoviruses which can be converted into tumor-specific OAs in the future. Adenovirus types marked in red (Ad5 and Ad3) were converted into OAs and also applied in the clinic. (b) To improve the efficacy of OAs and to arm novel OA candidates (AdX), diverse strategies were explored in clinical trials. Cytokine expression and release by OAs are able to stimulate immunity in the tumor microenvironment. Tumor-specific promoters, such as the hTERT promoter, guarantee tumor-specific replication of OAs and improve safety. The protein transduction domain (PTD) could penetrate cancer cells and enhance the transduction of OAs into cancer cells. Fiber modification such as the insertion of the tripeptide Arg-Gly-Asp (RGD) motif into the shaft of OAs, improves the binding of OAs to cancer cells. The enzyme hyaluronidase could be added as a transgene, which could degrade hyaluronic acid in the extracellular matrix and facilitate the spread of OAs through the tumor microenvironment. Furthermore, molecular evolution strategies can be applied. Other factors to consider are the administration route and the combination with conservative cancer therapies.