Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways

Background: The use of oncolytic viruses for treatment of cancer marks a significant alteration in the battle between host and virus. Viruses are confronted by cellular innate immune responses and contain an armamentarium of immunomodulatory proteins that suppress innate immunity. Tumorigenesis can result in impairment of innate immune responses. Viruses engineered to be vulnerable to normal responses may mediate tumor-specific killing with minimal off-target toxicity. Objective: To examine the mechanisms by which mammalian cells respond to viral infections in normal versus cancer cells and how viruses overcome these responses and to illustrate how this knowledge is used to develop physiologically targeted oncolytic viruses. Methods: Literature describing studies investigating innate responses to virus infections, cancer-specific molecular defects, immunosuppressive viral products and design of oncolytic viruses is extensively reviewed, and pertinent concepts are distilled and developed. Results/conclusion: Innate responses to viral infections are complex involving i) viral detection; ii) induction of interferon and other cytokines; and iii) establishment of an antiviral state. Oncolytic viruses are engineered to be susceptible to antiviral responses in normal cells. Cancers can be partially vulnerable to these viruses because they have defective antiviral responses but the antitumor potency of physiologically targeted viruses may be significantly diminished.