title: Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers.
abstract: Replication competent oncolytic herpes simplex viruses (HSV) with broad-spectrum activity against various cancers, including prostate cancer, exert a dual effect by their direct cytocidal action and by eliciting tumor-specific immunity. These viruses can deliver immunoregulatory molecules to tumors so as to enhance the cumulative antitumor response. This is particularly desirable for prostate cancers, which are usually poorly immunogenic. Initial studies described herein comparing the efficacy of three different oncolytic HSVs (G207, G47Delta, and NV1023) to inhibit the growth of the poorly immunogenic TRAMP-C2 mouse prostate tumors demonstrated that NV1023 was most effective in treating established tumors. The expression of IL-12 on an NV1023 background (NV1042), but not the expression of GM-CSF (NV1034), further enhanced the efficacy of NV1023 in two murine prostate cancer models with highly variable MHC class I levels, Pr14-2 with 91% and TRAMP-C2 with 2% of cells staining. NV1042 also inhibited the growth of distant noninoculated tumors in both prostate cancer models. NV1042 treated tumors exhibited increased immune cell infiltration and decreased levels of angiogenesis. Thus, an IL-12 expressing oncolytic herpes virus, which is capable of direct cytotoxicity and can modulate the otherwise suboptimal immune response through concomitant expression of the cytokine at the site of tumor destruction, could serve as a valuable clinical agent to seek out both overt and occult prostate cancers.
authors.affiliation: Department of Neurosurgery, Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Charlestown, 02129, USA.
authors.forename: S
authors.initials: S
authors.lastname: Varghese
authors.forename: S D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.forename: P G
authors.initials: PG
authors.lastname: Nielsen
authors.forename: T
authors.initials: T
authors.lastname: Ipe
authors.forename: R L
authors.initials: RL
authors.lastname: Martuza
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D005805:Genes, MHC Class I / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000472:pathogenicity; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor