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Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells.

Publication ,  Journal Article
Walton, RW; Brown, MC; Sacco, MT; Gromeier, M
Published in: J Virol
October 1, 2018

We are pursuing cancer immunotherapy with a neuro-attenuated recombinant poliovirus, PVSRIPO. PVSRIPO is the live attenuated type 1 (Sabin) poliovirus vaccine carrying a heterologous internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). Intratumoral infusion of PVSRIPO is showing promise in the therapy of recurrent WHO grade IV malignant glioma (glioblastoma), a notoriously treatment-refractory cancer with dismal prognosis. PVSRIPO exhibits profound cytotoxicity in infected neoplastic cells expressing the poliovirus receptor CD155. In addition, it elicits intriguing persistent translation and replication, giving rise to sustained type I interferon (IFN)-dominant proinflammatory stimulation of antigen-presenting cells. A key determinant of the inflammatory footprint generated by neoplastic cell infection and its role in shaping the adaptive response after PVSRIPO tumor infection is the virus's inherent relationship to the host's innate antiviral response. In this report, we define subversion of innate host immunity by PVSRIPO, enabling productive viral translation and cytopathogenicity with extremely low multiplicities of infection in the presence of an active innate antiviral IFN response.IMPORTANCE Engaging innate antiviral responses is considered key for instigating tumor-antigen-specific antitumor immunity with cancer immunotherapy approaches. However, they are a double-edged sword for attempts to enlist viruses in such approaches. In addition to their role in the transition from innate to adaptive immunity, innate antiviral IFN responses may intercept the viral life cycle in cancerous cells, prevent viral cytopathogenicity, and restrict viral spread. This has been shown to reduce overall antitumor efficacy of several proposed oncolytic virus prototypes, presumably by limiting direct cell killing and the ensuing inflammatory profile within the infected tumor. In this report, we outline how an unusual recalcitrance of polioviruses toward innate antiviral responses permits viral cytotoxicity and propagation in neoplastic cells, combined with engaging active innate antiviral IFN responses.

Duke Scholars

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

October 1, 2018

Volume

92

Issue

19

Location

United States

Related Subject Headings

  • Virology
  • Receptors, Virus
  • Poliovirus
  • Oncolytic Viruses
  • Interferon-Induced Helicase, IFIH1
  • Interferon Type I
  • Immunity, Innate
  • Humans
  • Glioblastoma
  • Cell Line, Tumor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Walton, R. W., Brown, M. C., Sacco, M. T., & Gromeier, M. (2018). Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells. J Virol, 92(19). https://doi.org/10.1128/JVI.00879-18
Walton, Ross W., Michael C. Brown, Matthew T. Sacco, and Matthias Gromeier. “Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells.J Virol 92, no. 19 (October 1, 2018). https://doi.org/10.1128/JVI.00879-18.
Walton RW, Brown MC, Sacco MT, Gromeier M. Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells. J Virol. 2018 Oct 1;92(19).
Walton, Ross W., et al. “Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells.J Virol, vol. 92, no. 19, Oct. 2018. Pubmed, doi:10.1128/JVI.00879-18.
Walton RW, Brown MC, Sacco MT, Gromeier M. Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells. J Virol. 2018 Oct 1;92(19).

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

October 1, 2018

Volume

92

Issue

19

Location

United States

Related Subject Headings

  • Virology
  • Receptors, Virus
  • Poliovirus
  • Oncolytic Viruses
  • Interferon-Induced Helicase, IFIH1
  • Interferon Type I
  • Immunity, Innate
  • Humans
  • Glioblastoma
  • Cell Line, Tumor