Replicative Conditioning of Herpes Simplex Type 1 Virus by Survivin Promoter, Combined to ERBB2 Retargeting, Improves Tumour Cell-restricted Oncolysis

Overview

Journal Sci Rep

Specialty Science

Date 2020 Mar 11

PMID 32152425

Citations 19

Authors

Emanuele Sasso

Guendalina Froechlich

Gabriella Cotugno

Anna Morena DAlise

Chiara Gentile

Veronica Bignone

Maria De Lucia

Biljana Petrovic

Gabriella Campadelli-Fiume

Elisa Scarselli

Alfredo Nicosia

Nicola Zambrano

Affiliations

Soon will be listed here.

Abstract

Oncolytic virotherapy is emerging as a promising therapeutic option for solid tumours. Several oncolytic vectors in clinical testing are based on attenuated viruses; thus, efforts are being taken to develop a new repertoire of oncolytic viruses, based on virulent viral genomes. This possibility, however, raises concerns dealing with the safety features of the virulent phenotypes. We generated a double regulated Herpes simplex type-1 virus (HSV-1), in which tumour cell restricted replicative potential was combined to selective entry via ERBB2 receptor retargeting. The transcriptional control of the viral alpha4 gene encoding for the infected cell protein-4 (ICP4) by the cellular Survivin/BIRC5 promoter conferred a tumour cell-restricted replicative potential to a virulent HSV-1 genome. The combination of the additional ERBB2 retargeting further improved the selectivity for tumour cells, conferring to the double regulated virus a very limited ability to infect and propagate in non-cancerous cells. Accordingly, a suitable replicative and cytotoxic potential was maintained in tumour cell lines, allowing the double regulated virus to synergize in vivo with immune checkpoint (anti-PD-1) blockade in immunocompetent mice. Thus, restricting the replicative spectrum and tropism of virulent HSV-1 genomes by combination of conditional replication and retargeting provides an improved safety, does not alter the oncolytic strength, and is exploitable for its therapeutic potential with immune checkpoint blockade in cancer.

Citing Articles

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The common H232 STING allele shows impaired activities in DNA sensing, susceptibility to viral infection, and in monocyte cell function, while the HAQ variant possesses wild-type properties.

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