The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

Abstract

Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy /virotherapy strategies may provide new options for the treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling the treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.

Keywords: Adenovirus library screening; Cox-2 promoter; Fiber-modified Ad; Oncolytic Adenovirus; Pancreatic cancer.

Figure 1. Non-replicative and replicative systems for cancer gene therapy

Compared to conventional cancer gene therapy with replication deficient adenovirus vector system (upper panel), a replicative vector system (lower panel) permitting tumor-selective replication and exponential spread of the progeny vector laterally in the tumors facilitates a dramatic amplification of the therapeutic effect, while keeping non-target cell unaffected thanks to replication selectivity.

Figure 2. Control mechanisms of oncolytic adenovirus

(A). Deletion type CRAds: this type of CRAd has a mutation/deletion in a region crucial for viral replication. While cancer cells possess the cellular environment to compensate the missing function of the virus, normal cells do not have that capability. For example, ONYX-015 (dl1520) and AdΔ24 were designed to replicate only in p53 and pRb mutated cells, respectively. (B). Selective promoter-based CRAd: A tumor/tissue specific promoter controls the expression of viral genes crucial for replication. As a result, the virus can replicate only in cells in which the promoter is active. By using a promoter with a tumor-ON/normal cell-OFF profile, the replication can be restricted to cancer cells.

Figure 3. Modification of adenovirus to achieve CAR-independent transduction

To achieve CAR-independent transduction, several modification strategies have been employed in adenovirus. (A) Poor infectivity of CAR negative cells with conventional Ad system, (B) fiber modification, (C) switching serotypes, (D) chimeric, (E) mosaic, and (F) bridging molecule-based targeting.

Figure 4. Novel system for adenovirus vector production

(A) Structure of Ad library with random 7 amino acid in the AB-loop of fiber-knob region. (B) High- diversity Ab library was produced with the newly developed rescue virus system by CRE-lox recombination in CRE-expressing, fiber-transcomplementing cell line (293CRE-69cell). The shuttle plasmid coding fiber library has a single loxP site in the upstream of the fiber gene. The produced library viruses were harvested 48 hours after shuttle plasmid transfection and rescue virus infection. (C)the strategy of replication-based Ad library screening [43].

Figure 5. Oncolytic virus targeting at three levels

The oncolytic viruses can be targeted at 3 levels: the first is organ level targeting which allows the administered virus delivered selectively to the target tumor region, the second is in situ level targeting enabling selective infection of the cancer cells, and the third is replication level control to provide cancer cell selective viral replication.