ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties
- PMID:12595888
- DOI: 10.1038/sj.gt.3301885
ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties
Abstract
Herpes simplex virus type-1 (HSV1) in which the neurovirulence factor ICP34.5 is inactivated has been shown to direct tumour-specific cell lysis in several tumour models. Such viruses have also been shown to be safe in Phase I clinical trials by intra-tumoral injection in glioma and melanoma patients. Previous work has used serially passaged laboratory isolates of HSV1 which we hypothesized may be attenuated in their lytic capability in human tumour cells as compared to more recent clinical isolates. To produce ICP34.5 deleted HSV with enhanced oncolytic potential, we tested two clinical isolates. Both showed improved cell killing in all human tumour cell lines tested compared to a laboratory strain (strain 17+). ICP34.5 was then deleted from one of the clinical isolate strains (strain JS1). Enhanced tumour cell killing with ICP34.5 deleted HSV has also been reported by the deletion of ICP47 by the up-regulation of US11 which occurs following this mutation. Thus to further improve oncolytic properties, ICP47 was removed from JS1/ICP34.5-. As ICP47 also functions to block antigen processing in HSV infected cells, this mutation was also anticipated to improve the immune stimulating properties of the virus. Finally, to provide viruses with maximum oncolytic and immune stimulating properties, the gene for human or mouse GM-CSF was inserted into the JS1/34.5-/47- vector backbone. GM-CSF is a potent immune stimulator promoting the differentiation of progenitor cells into dendritic cells and has shown promise in clinical trials when delivered by a number of means. Combination of GM-CSF with oncolytic therapy may be particularly effective as the necrotic cell death accompanying virus replication should serve to effectively release tumour antigens to then induce a GM-CSF-enhanced immune response. This would, in effect, provide an in situ, patient-specific, anti-tumour vaccine. The viruses constructed were tested in vitro in human tumour cell lines and in vivo in mice demonstrating significant anti-tumour effects. These were greatly improved compared to viruses not containing each of the modifications described. In vivo, both injected and non-injected tumours showed significant shrinkage or clearance and mice were protected against re-challenge with tumour cells. The data presented indicate that JS1/ICP34.5-/ICP47-/GM-CSF acts as a powerful oncolytic agent which may be appropriate for the treatment of a number of solid tumour types in man.
Similar articles
- Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect.Choi KJ, Kim JH, Lee YS, Kim J, Suh BS, Kim H, Cho S, Sohn JH, Kim GE, Yun CO.Choi KJ, et al.Gene Ther. 2006 Jul;13(13):1010-20. doi: 10.1038/sj.gt.3302759. Epub 2006 Mar 9.Gene Ther. 2006.PMID:16525479
- Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus.Kohno SI, Luo C, Nawa A, Fujimoto Y, Watanabe D, Goshima F, Tsurumi T, Nishiyama Y.Kohno SI, et al.Cancer Gene Ther. 2007 Nov;14(11):918-26. doi: 10.1038/sj.cgt.7701070. Epub 2007 Aug 10.Cancer Gene Ther. 2007.PMID:17693992
- An oncolytic HSV-1 mutant expressing ICP34.5 under control of a nestin promoter increases survival of animals even when symptomatic from a brain tumor.Kambara H, Okano H, Chiocca EA, Saeki Y.Kambara H, et al.Cancer Res. 2005 Apr 1;65(7):2832-9. doi: 10.1158/0008-5472.CAN-04-3227.Cancer Res. 2005.PMID:15805284
- Oncolytic herpes simplex virus vectors for cancer virotherapy.Varghese S, Rabkin SD.Varghese S, et al.Cancer Gene Ther. 2002 Dec;9(12):967-78. doi: 10.1038/sj.cgt.7700537.Cancer Gene Ther. 2002.PMID:12522436Review.
- Rethinking herpes simplex virus: the way to oncolytic agents.Campadelli-Fiume G, De Giovanni C, Gatta V, Nanni P, Lollini PL, Menotti L.Campadelli-Fiume G, et al.Rev Med Virol. 2011 Jul;21(4):213-26. doi: 10.1002/rmv.691. Epub 2011 May 27.Rev Med Virol. 2011.PMID:21626603Review.
Cited by
- Cancer immunotherapy turns viral.Galluzzi L, Lugli E.Galluzzi L, et al.Oncoimmunology. 2013 Apr 1;2(4):e24802. doi: 10.4161/onci.24802.Oncoimmunology. 2013.PMID:23734338Free PMC article.No abstract available.
- Single-cell transcriptomics of peripheral blood reveals anti-tumor systemic immunity induced by oncolytic virotherapy.Wu Q, Hu X, Zhang X, Kong D, Yang Z, Li G, Gu Z, Zhang Q, Wan D, Cheng S, Liu B, Zhang K, Zhang W.Wu Q, et al.Theranostics. 2022 Oct 17;12(17):7371-7389. doi: 10.7150/thno.74075. eCollection 2022.Theranostics. 2022.PMID:36438484Free PMC article.
- Tumor Tropism of DNA Viruses for Oncolytic Virotherapy.Enow JA, Sheikh HI, Rahman MM.Enow JA, et al.Viruses. 2023 Nov 16;15(11):2262. doi: 10.3390/v15112262.Viruses. 2023.PMID:38005938Free PMC article.Review.
- Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial.Andtbacka RH, Ross M, Puzanov I, Milhem M, Collichio F, Delman KA, Amatruda T, Zager JS, Cranmer L, Hsueh E, Chen L, Shilkrut M, Kaufman HL.Andtbacka RH, et al.Ann Surg Oncol. 2016 Dec;23(13):4169-4177. doi: 10.1245/s10434-016-5286-0. Epub 2016 Jun 24.Ann Surg Oncol. 2016.PMID:27342831Free PMC article.Clinical Trial.
- Oncolytic Viruses in the Era of Omics, Computational Technologies, and Modeling: Thesis, Antithesis, and Synthesis.Menotti L, Vannini A.Menotti L, et al.Int J Mol Sci. 2023 Dec 12;24(24):17378. doi: 10.3390/ijms242417378.Int J Mol Sci. 2023.PMID:38139207Free PMC article.Review.
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials