Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus

Abstract

An oncolytic virus (OV) based on poliovirus (PV), the highly attenuated polio/rhinovirus recombinant PVSRIPO, may deliver targeted inflammatory cancer cell killing; a principle that is showing promise in clinical trials for recurrent glioblastoma (GBM). The two decisive factors in PVSRIPO anti-tumor efficacy are selective cytotoxicity and its in situ immunogenic imprint. While our work is focused on what constitutes PVSRIPO cancer cytotoxicity, we are also studying how this engenders host immune responses that are vital to tumor regression. We hypothesize that PVSRIPO cytotoxicity and immunogenicity are inextricably linked in essential, complimentary roles that define the anti-neoplastic response. Herein we delineate mechanisms we unraveled to decipher the basis for PVSRIPO cytotoxicity and its immunotherapeutic potential.

Figure 1

Hypothetical model of PVSRIPO oncolytic immunotherapy mechanisms. A combination of (left) direct viral tumor cytotoxicity and engagement of Mda5/the anti-viral IFN response; and (middle) PVSRIPO non-lethal infection and pro-inflammatory stimulation of tumor-associated macrophages (TAM) and/or dendritic cells; (right) recruits immune effector responses directed against tumor neo-antigens.

Figure 2

CD155 expression is common in GBM. Primary patient explant GBM xenografts (passaged exclusively in mice) were harvested and lysed for immunoblot analysis. CD155 (variable electrophoretic mobility is due to distinct glycosylation patterns); PTEN; p-AKT(S473) and (T308); and GAPDH were analyzed by immunoblot.