Oncolytic Viruses and Immune Checkpoint Inhibition: The Best of Both Worlds

Abstract

Cancer immunotherapy and the emergence of immune checkpoint inhibitors have markedly changed the treatment paradigm for many cancers. They function to disrupt cancer cell evasion of the immune response and activate sustained anti-tumor immunity. Oncolytic viruses have also emerged as an additional therapeutic agent for cancer treatment. These viruses are designed to target and kill tumor cells while leaving the normal cells unharmed. As part of this process, oncolytic virus infection stimulates anti-cancer immune responses that augment the efficacy of checkpoint inhibition. These viruses have the capability of transforming a "cold" tumor microenvironment with few immune effector cells into a "hot" environment with increased immune cell and cytokine infiltration. For this reason, there are multiple ongoing clinical trials that combine oncolytic virotherapy and immune checkpoint inhibitors. This review will detail the key oncolytic viruses in preclinical and clinical studies and highlight the results of their testing with checkpoint inhibitors.

Keywords: immune checkpoint inhibitor; immunotherapy; oncolytic virus.

Figure 1

Timeline of FDA Approval of Immune Checkpoint Inhibitors

Figure 2

Immune Checkpoints and the Immune Responsiveness of a Tumor Microenvironment (Left) Immune checkpoints are triggered by ligand-receptor interactions (red box) wherein T cells are turned OFF making the tumor cold (escape immune response). (Right) Immune checkpoint inhibitors like antibodies, drugs, and recombinant forms of the ligands or the receptors block this ligand–receptor interaction allowing the T cell to turn ON (triggering immune response) and mount an immune response; hence, the cold tumor becomes hot.

Figure 3

Key Receptor-Ligand Interactions That Turn OFF the T Cell Oncolytic viruses induce immune responses that, upon infecting tumor cells, induce apoptosis or express the transgenes that, when presented or released by tumor cells, attract immune cells. The transgenes could be (1) key epitopes that attract immune cells, (2) immune-stimulatory blockers of immune checkpoints, or (3) key genes from non-human species that have anti-tumor effects.

Figure 4

Oncolytic Viruses Stimulate the Tumor Microenvironment and Synergize with ICI Schematic representation of different stages of tumor suppression using combination therapy involving oncolytic viruses (OVs) and immune checkpoint inhibitors. Initially, tumor cells are infected with OVs resulting in the release of cytokines, chemokines, and viral transgene which triggers immune responses. A further treatment of those infected cells with immune checkpoint inhibitors mount additional immune responses, resulting in the killing of most cancer cells.

Figure 5

Oncolytic Viral Means of Immune Stimulation Oncolytic viruses with different properties have a different mode of action on tumor cells. (1) Non-replicating OVs bearing engineered transgenes allow the infected tumor cells to express those transgenes that trigger an immune response. (2) Replicating OVs lyses the infected tumor cells after infection; the released virus infects the neighboring tumor cells, making the treatment effective. (3) Non-lytic viruses engineered with transgenes integrate the transgene into the tumor cell genome upon infection; the infected cells then express the transgenes and mount an immune response. Because of genome integration, progeny tumor cells are also mitigated, as the integrated transgene is transferred from parental cells to progeny cells.