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.
Highlights
Oncolytic virotherapy is emerging as a promising therapeutic option for solid tumours
In order to assess the extent of their cancer-restricted expression, we performed a Pan-Cancer analysis by the Cancer Genome Atlas (TCGA) Firebrowse Data portal (Institute TCGA Genome Data Analysis Center (2016): Firehose stddata__2017.9.24 run
By combining literature reports with bioinformatic tools of regulatory elements prediction (PROMO) and Encyclopedia of DNA Elements (ENCODE), we identified the putative promoter sequences for the three analysed genes in the regions −260 to −1 for Survivin/BIRC5, −400 to −24 for TERT, and −300 to −1 for CXCR438–44
Summary
Oncolytic virotherapy is emerging as a promising therapeutic option for solid tumours. Transgenic expression of GM-CSF represents an additional feature of T-VEC, conferring the ability to activate antigen-presenting cells (APC) within www.nature.com/scientificreports the tumour microenvironment[13] Despite these features, the need for a repertoire of viral vectors with improved properties stimulated the development of new strategies for oncolytic virotherapy, taking into account both safety and potency of oncolytic viruses. The insertion of sequences within relevant HSV-1 genes, targeted by miRNAs selectively expressed in normal cells, represents an additional strategy for limiting off-tumour replication of virulent oHSVs23 Combination of strategies, such as transcription and translation retargeting, have been exploited, in order to obtain tumour-specific oncolytic viruses[24,25]. Our data show that the added feature of cancer cell-restricted replicative potential to receptor retargeting may improve the safety feature of oncolytic virotherapy
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