Recombinant Poliovirus for Cancer Immunotherapy

Abstract

Mechanisms to elicit antiviral immunity, a natural host response to viral pathogen challenge, are of imminent 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 such ‘oncolytic’ viral agents to instigate antitumor immunity is not an easy feat. During co-evolution with their hosts, viruses 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 vs. viral immune evasion and suppression, determines the potential for antitumor immunity to occur. Moreover, paradigms of early host:virus relations established in normal immunocompetent organisms may not hold in the profoundly immunosuppressive tumor microenvironment. In this review, we explain the mechanisms of recombinant non-pathogenic poliovirus, PVSRIPO, which is currently in Phase-1 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.

Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials

“…These may be consulted for all the Institutional approvals for the trials and for the imaging. We do not describe the clinical trials and results: see, for example, [ 25 , 26 ] for the MR1-1 and D2C7 studies, respectively and [ 27 ] or [ 28 ], for the poliovirus studies. Our purpose here is simply the evaluation of the infusion model against the data and conclusions, subject to more testing in the future, so that we may draw from the simulations the relative importance of the different variables in determining the distributions of the (therapeutic) particles (molecules).…”

The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

“…This ability to change the TME makes them potentially powerful agents when concurrently used with other forms of immunotherapy, like checkpoint blockade [ 116 ]. Various types of oncolytic viruses are currently being studied, including herpes, poliovirus, adenovirus, cytomegalovirus (CMV), measles, coxsackie, parvovirus, and reovirus [ 113 , 117 , 118 , 119 ]. Historically, much work was done using herpes viruses as oncolytic therapy for malignant glioma [ 120 ].…”

Molecular stratifications, biomarker candidates and new therapeutic options in current medulloblastoma treatment approaches

“…Targeted elimination may also be achieved through the highly attenuated polio/rhinovirus recombinant PVSRIPO that recognizes the poliovirus receptor CD155 widely expressed by both cancerous cells and components of the tumor microenvironment [115]. A phase I dose-finding and toxicity study on adults with recurrent supratentorial WHO grade IV malignant gliomas treated by intratumoral delivery of the recombinant polio/rhinovirus chimera identified better survival outcome compared to historical controls [116].…”