Unleashing the therapeutic potential of oncolytic viruses

Abstract

Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved. These findings have implications for the optimization of oncolytic immunotherapy, at least that based on NDV, and further confirm that specific combinatorial approaches are promising for clinical development.

Figure 1. Schematic representation of how OVs influence various aspects of the cancer-immunity cycle.

Following tumor infection by an OV, the virus selectively replicates in tumors cells (i). The cells are lysed, resulting in immunogenic cell death and release of soluble virus- and tumor-specific antigens, danger-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), type 1 IFNs, and chemokines (ii), which help recruit and condition professional antigen-presenting cells such as DCs (iii). DCs migrate with antigen to regional lymph nodes, where they prime and activate virus- and tumor-specific T cells (iv). The chemokine gradient generated within the tumor microenvironment recruits antigen-specific T cells (v), and T cells mediate cytotoxic effector functions within the injected tumor (vi). The local cytokine profile can also increase PD-1 expression on T cells and PD-L1 expression on tumor cells (vii) as a counterregulatory measure, limiting immune responses but also rendering the tumors more susceptible to treatment with checkpoint blockade. In contrast to some intratumoral therapies, OVs can also result in trafficking of tumor-specific T cells to distant, uninjected tumors, where they can mediate antitumor activity (viii).