Stem Cell-Based Cell Carrier for Targeted Oncolytic Virotherapy: Translational Opportunity and Open Questions

Abstract

Oncolytic virotherapy for cancer is an innovative therapeutic option where the ability of a virus to promote cell lysis is harnessed and reprogrammed to selectively destroy cancer cells. Such treatment modalities exhibited antitumor activity in preclinical and clinical settings and appear to be well tolerated when tested in clinical trials. However, the clinical success of oncolytic virotherapy has been significantly hampered due to the inability to target systematic metastasis. This is partly due to the inability of the therapeutic virus to survive in the patient circulation, in order to target tumors at distant sites. An early study from various laboratories demonstrated that cells infected with oncolytic virus can protect the therapeutic payload form the host immune system as well as function as factories for virus production and enhance the therapeutic efficacy of oncolytic virus. While a variety of cell lineages possessed potential as cell carriers, copious investigation has established stem cells as a very attractive cell carrier system in oncolytic virotherapy. The ideal cell carrier desire to be susceptible to viral infection as well as support viral infection, maintain immunosuppressive properties to shield the loaded viruses from the host immune system, and most importantly possess an intrinsic tumor homing ability to deliver loaded viruses directly to the site of the metastasis-all qualities stem cells exhibit. In this review, we summarize the recent work in the development of stem cell-based carrier for oncolytic virotherapy, discuss the advantages and disadvantages of a variety of cell carriers, especially focusing on why stem cells have emerged as the leading candidate, and finally propose a future direction for stem cell-based targeted oncolytic virotherapy that involves its establishment as a viable treatment option for cancer patients in the clinical setting.

Keywords: cell carrier; oncolytic virus; stem cell.

Figure 1

Comparison of modified virus behavior in healthy cells and tumor cells along with mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Virus modification inhibits the ability of virus replication in healthy cells, eliminating the potential of widespread infection upon oncolytic virotherapy injections. However, injected viruses rapidly replicate in tumor cells, causing lysis of tumor cells. This allows the virus to destroy malignant cells and spread throughout the tumor population.

Figure 2

Antibodies react to the injection of naked viruses, prohibiting viruses from reaching the tumor site because of filtration by the liver. Contrastingly, injections of stem cells carrying modified viruses evade antibodies and T Cells because of the low amount of transporters associated with antigen processing (TAP) in stem cells. Stem cell carriers are not filtered to the liver and home directly to the tumor site. Upon reaching the tumor, stem cell carriers act as replication factories for viruses, prompting the release of numerous viruses directly into the tumor.