Expanding the Spectrum of Pancreatic Cancers Responsive to Vesicular Stomatitis Virus-Based Oncolytic Virotherapy: Challenges and Solutions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis and a dismal survival rate, expected to become the second leading cause of cancer-related deaths in the United States. Oncolytic virus (OV) is an anticancer approach that utilizes replication-competent viruses to preferentially infect and kill tumor cells. Vesicular stomatitis virus (VSV), one such OV, is already in several phase I clinical trials against different malignancies. VSV-based recombinant viruses are effective OVs against a majority of tested PDAC cell lines. However, some PDAC cell lines are resistant to VSV. Upregulated type I IFN signaling and constitutive expression of a subset of interferon-simulated genes (ISGs) play a major role in such resistance, while other mechanisms, such as inefficient viral attachment and resistance to VSV-mediated apoptosis, also play a role in some PDACs. Several alternative approaches have been shown to break the resistance of PDACs to VSV without compromising VSV oncoselectivity, including (i) combinations of VSV with JAK1/2 inhibitors (such as ruxolitinib); (ii) triple combinations of VSV with ruxolitinib and polycations improving both VSV replication and attachment; (iii) combinations of VSV with chemotherapeutic drugs (such as paclitaxel) arresting cells in the G2/M phase; (iv) arming VSV with p53 transgenes; (v) directed evolution approach producing more effective OVs. The latter study demonstrated impressive long-term genomic stability of complex VSV recombinants encoding large transgenes, supporting further clinical development of VSV as safe therapeutics for PDAC.

Keywords: oncolytic virus; pancreatic cancer; pancreatic ductal adenocarcinoma; vesicular stomatitis virus; virotherapy.

Figure 1

General Overview of Oncolytic Virotherapy. This figure demonstrates the general method of action for the treatment of cancer by oncolytic virotherapy using VSV as an oncolytic virus. The images depict the infection and oncolysis of malignant cells over time, followed by immunostimulation of cells invading the cleared area. The figure was created by authors with BioRender software (BioRender.com).

Figure 2

Permissiveness of PDAC to VSV: Four Different Phenotypes. This figure demonstrates the variability across PDAC in regard to permissiveness to infection by VSV. Permissiveness refers to the cells allowance for viral attachment, infection, and replication. The figure was created by authors with BioRender software (BioRender.com).

Figure 3

Syngeneic Model of PDAC in Mice. This figure shows the method of development for the murine model of PDAC. In this model, C57BL6 mice are used both for the development of the tumors and to evaluate the treatment in vivo. The figure was created by authors with BioRender software (BioRender.com).