Current strategies to circumvent the antiviral immunity to optimize cancer virotherapy

Abstract

Cancer virotherapy is a paradigm-shifting treatment modality based on virus-mediated oncolysis and subsequent antitumor immune responses. Clinical trials of currently available virotherapies showed that robust antitumor immunity characterizes the remarkable and long-term responses observed in a subset of patients. These data suggest that future therapies should incorporate strategies to maximize the immunotherapeutic potential of oncolytic viruses. In this review, we highlight the recent evidence that the antiviral immunity of the patients may limit the immunotherapeutic potential of oncolytic viruses and summarize the most relevant approaches to strategically redirect the immune response away from the viruses and toward tumors to heighten the clinical impact of viro-immunotherapy platforms.

Keywords: central nervous system neoplasms; immunotherapy; oncolytic virotherapy; oncolytic viruses.

Figure 1

Methods to circumvent antiviral immunity. Oncolytic viruses (OVs) exert their effect by infecting the cancer cells, replicating, and inducing oncolysis. Iimmunogenic cell death of the tumor subsequently activates anti-viral and anti-tumor T cells. However, viral activity is limited by the humoral, innate and adaptive cellular immune components of the host. Several approaches aim to counteract each arm of the immune system to protect the viruses and maximize tumor regression. OVs can be shielded from the humoral immune responses of B cells and the complement pathway through encapsulation OVs in protective coatings and cellular carriers, genetic modification of the viral capsid to reduce expression of common viral epitopes, and administration of bispecific engagers that can bind neutralizing antibodies and tumors cells on different ends. To confer OVs stealth characteristic, the innate immunity can be tamed through the inhibition of the anti-viral interferon (IFN) pathway, the natural killer cells and antigen presentation. T cell immunodominance from viral antigens can be overcome through nanoparticle-enveloped viral antigens and tolerogenic dendritic cells. ISG, interferon-stimulated gene; ISRE, interferon-stimulated response element; MHC, major histocompatibility complex; NK, natural killer; TAP, transporter associated with antigen processing.