Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing.
Oncolytic herpes simplex virus type 1 (HSV-1) vectors are promising therapeutic agents for cancer. Their efficacy depends on the extent of both intratumoral viral replication and induction of a host antitumor immune response. To enhance these properties while employing ample safeguards, two conditionally replicating HSV-1 vectors, termed G47Delta and R47Delta, have been constructed by deleting the alpha47 gene and the promoter region of US11 from gamma34.5-deficient HSV-1 vectors, G207 and R3616, respectively. Because the alpha47 gene product is responsible for inhibiting the transporter associated with antigen presentation (TAP), its absence led to increased MHC class I expression in infected human cells. Moreover, some G47Delta-infected human melanoma cells exhibited enhanced stimulation of matched antitumor T cell activity. The deletion also places the late US11 gene under control of the immediate-early alpha47 promoter, which suppresses the reduced growth properties of gamma34.5-deficient mutants. G47Delta and R47Delta showed enhanced viral growth in a variety of cell lines, leading to higher virus yields and enhanced cytopathic effect in tumor cells. G47Delta was significantly more efficacious in vivo than its parent G207 at inhibiting tumor growth in both immune-competent and immune-deficient animal models. Yet, when inoculated into the brains of HSV-1-sensitive A/J mice at 2 x 10(6) plaque forming units, G47Delta was as safe as G207. These results suggest that G47Delta may have enhanced antitumor activity in humans.
Todo
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Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. todo@helix.mgh.harvard.edu
Martuza
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Rabkin
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Johnson
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D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002522:Chlorocebus aethiops; D003257:Consumer Product Safety; D003588:Cytopathogenic Effect, Viral; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D005910:Glioma / Q000276:immunology / Q000517:prevention & control*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000276:immunology / Q000517:prevention & control*; D016601:RNA-Binding Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication
D015395:Histocompatibility Antigens Class I; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; D014764:Viral Proteins