Recombinant Poliovirus for Cancer Immunotherapy

Abstract

Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of eminent relevance to cancer immunotherapy. "Oncolytic" viruses, naturally existing or genetically engineered viral agents with cell type-specific propagation in malignant cells, were ostensibly conceived for their tumor cytotoxic properties. Yet, their true therapeutic value may rest in their ability to provoke antiviral signals that engage antitumor immune responses within the immunosuppressive tumor microenvironment. Coopting oncolytic viral agents to instigate antitumor immunity is not an easy feat. In the course of coevolution with their hosts, viruses have acquired sophisticated strategies to block inflammatory signals, intercept innate antiviral interferon responses, and prevent antiviral effector responses, e.g., by interfering with antigen presentation and T cell costimulation. The resulting struggle of host innate inflammatory and antiviral responses versus viral immune evasion and suppression determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus interaction established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant nonpathogenic poliovirus, PVSRIPO, which is currently in phase I clinical trials against recurrent glioblastoma. We focus on an unusual host:virus relationship defined by the simple and cytotoxic replication strategy of poliovirus, which generates inflammatory perturbations conducive to tumor antigen-specific immune priming.

Keywords: CD155; cancer immunotherapy; interferon; internal ribosomal entry site; neutrophils; poliovirus.

Figure 1

Immunohistochemistry for the PV receptor (CD155) in 19 triple-negative breast cancer cases. For methods and detailed information on the assay, expression scoring, etc. see Chandramohan et al. (9). The table summarizes expression scores in the 19 cases. The numbered panels show IHC results for the corresponding cases in the table. Size bars represent 1 mm (7, 14) or 100 μm (4, 8, 10, 17).

Figure 2

PVSRIPO replication induces type I IFN responses and profound neutrophil invasion in a breast cancer xenotransplantation model (SUM149) (6). A. Infection of SUM149 (triple negative breast cancer) cells with PVSRIPO at a multiplicity of infection (MOI) of 0.1 causes prototypical signs of active viral translation (viral proteins 2BC/2C), viral cytopathogenic damage (eIF4G cleavage), and the type 1 IFN response (induction of ISGs IFIT1 and ISG15). At later intervals post infection (72 hrs), there is global loss of the proteome (see the GAPDH loading control) due to sweeping destruction of cancer cells. B–E. Immunohistochemistry for CD11b, a marker of myeloid cells, in SUM149 xenotransplanted tumors in athymic mice. These cells were determined to be largely neutrophils via flow cytometry [CD11b+, F4/80 negative, Ly6C+, Ly6G+ (6)]. Tumors in mock-treated animals (B; see detail at higher magnification in D) contain minimal neutrophil infiltrates. In contrast, PVSRIPO-treated tumors exhibit massive neutrophil invasion (C; see detail at higher magnification in E). For methods and detailed information on the assay, the xenotransplantation model, etc. see Holl et al. (6). Size bars represent 500 μm (B, C) or 100 μm (D, E).