Oncolytic Viruses-Natural and Genetically Engineered Cancer Immunotherapies

Abstract

There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.

Keywords: cancer immunotherapy; oncoimmunology; oncolytic viruses; pathogens; viruses.

Figure 1

Considerations in the development of oncolytic viruses (OVs). Considerations in the development of efficacious OV immunotherapy include targeting, mechanism of action, and pharmacodynamics. Targeting (blue box) is dependent on the natural and engineered tropism of viruses for tumor vs. normal cells. The mechanism of action (red box) of OVs is dependent on the immune mechanisms and the non-immune mechanisms of OVs, which are further enhanced by the combination of OVs with traditional and emerging antitumor therapeutics. OVs share pharmacodynamic considerations (orange box) with other small molecule drugs as well as raise new fundamental issues in terms of bioavailability vs. clearance and barriers to safety vs. efficiency. Overlapping arrow colors signify the existent overlap between the listed considerations.

Figure 2

Pathways, receptors, and mechanisms used by oncolytic viruses (OVs) to target cancer cells. OVs target cancer cells through pathways, receptors, and mechanisms used to promote tumor growth, including immune-avoidance mechanisms, extracellular oncogenic receptors, and intracellular oncogenic pathways. Immune-avoidance, extracellular receptor, and intracellular pathway targets that are overexpressed or repressed to inherently allow tumors to avoid immune responses can simultaneously can be used for targeting OVs to cancer cells. Extracellular receptors include surface molecules [such as integrins, ICAMs, and others (CD155, laminin receptors, etc.)] inherently expressed by some tumor cells, which are utilized by viruses for specific targeting to cancer cells rather than normal cells. Intracellular pathways are utilized in tumor cells to promote proliferation and survival, which are required for viral propagation, thus enhancing cancer cell susceptibility to oncolytic viral infection. Single examples of viruses utilizing each of the described targets are listed in black text. Mechanisms, pathways, and receptors that enhance cancer cell targeting as part of the natural tropisms of OVs are listed in white text and as part of the engineered tropisms of OVs are listed in red text.

Figure 3

Mechanisms of action underlying the efficacy of oncolytic viruses (OVs). Mechanistic pathways are categorized as immune-mediated and non-immune pathways. Non-immune pathways are utilized by OVs to avoid apoptotic (non-immunogenic) death to allow sufficient viral infectivity and spread, while at the same time resulting in cell lysis. Connecting non-immune and immune pathways is antigen release as a result of viral infection-induced cell lysis. The mechanism underlying immune-mediated pathways includes delivery or utilization of immune mediators that allow for improved tumor antigen presentation and subsequent tumor-targeted immune responses. Radiation therapy and chemotherapy (leading to cell lysis and antigen release) and immunotherapy (leading to blockade of antitumor response suppression and exhaustion) are being combined with OVs to simultaneously target multiple mechanistic pathways for improved antitumor therapeutic responses. Mechanisms of action are listed in red text. Single examples of viruses utilizing each of the described mechanisms are listed in black text next to their respective mechanism. Mediators responsible for each mechanism are listed in blue text next to their respective mechanism. Therapies used in combination regimens with OVs are listed in green text.