Oncolytic viruses (OVs) are a promising treatment for solid tumors. When injected into tumors, oncolytic viruses are able to selectively target cancer cells without affecting normal cells, causing cancer cell lysis by replicating within the cancer cells. They can also further trigger a systemic immune response to kill cancer cells. Oncolytic viral therapy has emerged as a promising cancer treatment modality.
Currently, four oncolytic viral therapies have been approved for the treatment of melanoma, colorectal cancer, malignant glioma and many other malignancies by intratumoral injection. However, this intratumoral route of administration has limited the widespread use of oncolytic viral therapies.
Systemic delivery of oncolytic virus allows easier access to a wide spectrum of tumor lesions, but poses substantial problems. Oncolytic virus particles exposed in the blood are rapidly inactivated by complement proteins, neutralized by antibodies, and eliminated by the reticuloendothelial system. After systemic administration, the half-life of natural lysing adenovirus is less than 2 minutes, making it rare for the virus to reach the target site.
Recently, Professor Zhen Gu’s team at Zhejiang University College of Pharmacy published a paper in Advanced Materials titled “Inhibition of Tumor Metastasis by Liquid Nitrogen-Shocked Tumor Cells with Oncolytic Viruses Infection”.
The study describes a virus-hidden tumor targeting strategy that allows lysing viruses to be delivered to lung metastases via systemic administration. Oncolytic virusescan actively infected, internalized, and cloaked within tumor cells, which are subsequently treated with liquid nitrogen shock to eliminate their pathogenicity. This Trojan horse-like vector avoids the neutralization and clearance of oncolytic viruses in the bloodstream and facilitates tumor-targeted delivery, resulting in more than 110-fold viral enrichment in tumor metastases.
This strategy could be employed as a novel tumor vaccine to initiate endogenous adaptive antitumor effects by enhancing memory T cell subtypes and modulating the tumor immune microenvironment, including M2 macrophage reduction, Treg cell downregulation, and T cell initiation enhancement.
Despite their tumor-selective lytic effects, systemic administration of lysing viruses faces challenges such as limited cycling cycles, poor tumor targeting, and spontaneous antiviral immune responses.
This study reports a Trojan horse-like approach that effectively targets delivery of oncolytic adenovirus type 11 (Ad11) to tumor metastases and effectively inhibits tumor progression after intravenous administration.
Oncolytic viruses can be internalized into tumor cells through CD46-mediated endocytosis. The pathogenicity of tumor cells is eliminated using liquid nitrogen shock without sacrificing oncolytic virus activity and infectivity. When exposed to blood after intravenous delivery, liquid nitrogen-treated tumor cells (LNT) prevent oncolytic virus from fast neutralization and eradication.
Surface ligands and receptors, such as CD44 and E-Cadherin, as well as enhanced pulmonary capillary blockade due to micrometer size, promote LNT-Ad11 accumulation in metastatic lesions. In this way, LNT-Ad11 obtained more than 110-fold enrichment in lung metastatic tumors compared to direct injection of unspecifically treated oncolytic virus. Tumor progression was suppressed and immune response was boosted as a result of local Ad11 enrichment.
Overall, this study developed a virus-hidden tumor targeting strategy that allows oncolytic virus to be delivered to lung metastatic tumors via systemic administration. The oncolytic virus can be actively infected, internalized, and cloaked within tumor cells, which are then treated with liquid nitrogen shock to eliminate their pathogenicity. This Trojan horse-like vector avoids viral neutralization and clearance from the bloodstream and facilitates targeted delivery to the tumor site.
Reference
1. Wu, Qing, et al. “Inhibition of tumor metastasis by liquid‐nitrogen‐shocked tumor cells with oncolytic viruses infection.” Advanced Materials 35.28 (2023): 2212210.