Oncolytic Viruses and Their Application to Cancer Immunotherapy

Abstract

Oncolytic viruses (OVs) selectively replicate in and kill cancer cells, and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer-selective or can be genetically-engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines, and can be armed with immune modulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy; they include: (i) innate immune responses and the degree of inflammation induced, (ii) types of virus-induced cell death, (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture, and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers (MHC, co-stimulatory, NK receptors), and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing GM-CSF, have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between anti-virus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs.

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

“…OVs have many features that make them advantageous for cancer immunotherapy: (1) there is a very low probability for the generation of resistance to virus (not seen so far), because OVs often target multiple oncogenic pathways and induce cytotoxicity in different ways, (2) they are nonpathogenic, replicate, and destroy cancer cells, (3) virus dose in the tumor increases with time due to in situ virus amplification, which is opposite to classical drug pharmacokinetics that decreases with time, and (4) OVs can be manipulated to include safety features such as drug and immune sensitivity allowing to control them [50]. Intratumoral delivery of the OVs can be a good strategy to minimize the sequestration of the virus in the spleen and liver as well as antiviral response [26].…”

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…With the advent and clinical successes of anticancer immunotherapeutic agents, there is increasing interest in understanding the immune-mediated component of oncolytic virotherapy (54). Viral infections commonly elicit an inflammatory response marked by the release of cytokines and chemokines and a coordinated action between innate and adaptive immune cells.…”

Current State of Immune-Based Therapies for Glioblastoma

“…27 Two main types of viruses are used in this technology: replicationdefective vectors, in which viral genes have been removed so there is no expression of viral genes or generation of progeny viruses, but there is expression of an immunostimulatory and/or cytotoxic gene, and tumor replication-selective viruses (oncolytic viruses), in which a viral pathogen is engineered so that its pathogenicity is now targeted to tumor cells and not normal cells. 28 It is recognized now that the presence of viral genes and viral proteins in both of these technologies can elicit powerful anticancer immune responses, which are a major component of efficacy.…”