Oncolytic polio virotherapy of cancer

Abstract

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Keywords: CD155; eIF4G; innate antiviral response; interferon; internal ribosomal entry site; nectin-like molecule 5; oncolytic virus; poliovirus; translation.

Figure 1

Genetic structure of PVSRIPO. Poliovirus has a single-strand, +sense RNA genome of ~7,400 nucleotide length; overall genome organization is outlined (ORF; open reading frame). (A) Poliovirus type 1 (Mahoney), isolated 1941 from stool of healthy children in Cleveland, is the prototype neurovirulent strain. The approximate binding region for the eIF4G:4A:4B translation initiation helicase complex in the internal ribosomal entry site (IRES) is indicated. (B) Serial passage in primate tissue culture/primates yielded the type 1 (Sabin) live-attenuated vaccine. The position of a key attenuating point mutation in the IRES (G480A) is shown (•). (C) PVSRIPO is the type 1 (Sabin) vaccine containing a human rhinovirus type 2 IRES (pink box; a region of major sequence divergence is shaded darker).

Figure 2

Early events after PVSRIPO infection of tumor cells. (A) Approximately 15min after virus-receptor docking, empty capsids (indicating viral RNA ‘uncoating’) can be recovered from infected cells. (B) The incoming, uncapped viral RNA serves as a translation template; recruitment of the host cell translation initiation helicase complex eIF4G:4A:4B to the IRES is required for initiation of viral protein synthesis (see text). (C) The first protein released from the nascent viral polyprotein is the viral protease 2A. (D) Initial rounds of viral translation give rise to highly productive viral protein synthesis and genome replication. This is fostered by stimulatory viral polypeptides and block of competing host cell protein synthesis. (E) Viral progeny is first detected by ~4h.

Figure 3

The effect of innate anti-viral activation on PVSRIPO oncolysis in vitro. (A) Schematic of the RIG-I like receptors and MDA-5 activation, IFN induction by polio RNA. (B) DM443 and (C) DM440 cultures were infected with PVSRIPO at an MOI of 0.1. In DM443 cells (B), stable levels of Stat1 phosphorylation indicate failure of type 1 IFN signaling. DM440 cells responded with vigorous Stat1 phosphorylation (red arrowheads) (C). Viral cell killing (indicated by eIF4G cleavage) and expression of viral proteins (2C) were indistinguishable in both cell lines. The relatively protracted appearance of viral proteins/eIF4G cleavage is due to the low MOI.

Figure 4

Possible host immunogenic responses to PVSRIPO oncolytic immunotherapy. (Left) PVSRIPO infects and kills GBM cells, elicits ICD, presents DAMPs and tumor antigens. (Middle) PVSRIPO-infection of APCs elicits innate antiviral type 1 IFN responses, PAMP signals for pro-inflammatory stimulation. (Right) The combination of multiplex direct viral cytotoxicity, DAMP and PAMP presentation, pro-inflammatory TAM activation, cytokine release, etc. promote an adaptive anti-tumor immune effector cell response.