Combination of Mesenchymal Stem Cell-Delivered Oncolytic Virus with Prodrug Activation Increases Efficacy and Safety of Colorectal Cancer Therapy

Abstract

Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.

Molecular Circuits of Immune Sensing and Response to Oncolytic Virotherapy

“…Utilizing tumor-specific promoters such as CXCR4-promoter allows for tumor-specific transgene expression, driving high expression of therapeutic genes like GM-CSF and B7-1, thereby enhancing immune cell activation and infiltration into tumors [71,102]. Various delivery strategies, including gelatin gel-mediated co-delivery and mesenchymal stem cell-mediated delivery, improve the sustained release and tumor targeting of oncolytic adenoviruses, thereby enhancing their therapeutic efficacy [103,104].…”

Mesenchymal stem cell-released oncolytic virus: an innovative strategy for cancer treatment

“…Combining MSC-delivered OV with prodrug activation is another strategy to achieve optimum effectiveness. Under these circumstances, MSCs might convert the simultaneously delivered prodrug into cytotoxic metabolites, causing oncolysis and inhibiting tumor development without being hazardous to the host's essential organs [ 195 ].…”

The Roles of Mesenchymal Stem Cells in Gastrointestinal Cancers

“…Babaei et al found that MSCs carrying oncolytic reovirus would enhance the anti-tumor activity of a mouse model of CRC (107). Additionally, it was showed that the combination of oncolytic virus delivered by MSCs and prodrug activation could inhibit tumor growth without causing toxicity to the host's vital organs, which would improve the effectiveness and safety of CRC treatment and present a new method for the development of oncolytic virus therapies for cancers (108).…”