title: Role of the immune response during neuro-attenuated herpes simplex virus-mediated tumor destruction in a murine intracranial melanoma model.
abstract: Neuro-attenuated herpes simplex virus-1 (HSV-1) gamma34.5 mutants can slow progression of preformed tumors and lead to complete regression of some tumors. However, the role of the immune response in this process is poorly understood. Syngenic DBA/2 tumor-bearing mice treated with HSV-1 1716 fourteen days after tumor implantation had significant prolongation in survival when compared with mice treated with viral growth sera (mock; 38.9 +/- 2.3 versus 24.9 +/- 0.6, respectively; P < 0.0001). Additionally, 60% of the animals treated on day 7 had complete regression of the tumors. However, no difference was observed in the mean survival rates of viral- or mock-treated tumor-bearing SCID mice (15 +/- 1.7 versus 14.8 +/- 2.2, respectively). When DBA/2 mice syngenic for the tumor were depleted of leukocytes by cyclophosphamide administration (before and during viral administration), there was again no significant difference observed in the survival times (19.0 +/- 1.9 versus 19.5 +/- 2.7, respectively). These data demonstrate that the immune response contributes to the viral-mediated tumor destruction and the increase in survival. Immune cell infiltration was up-regulated, specifically CD4+ T cells and macrophages (which are found early after viral administration). Prior immunity to HSV-1 increased survival times of treated mice over those of naive mice, an important consideration because 50-95% of the adult human population is sero-positive for HSV-1. Our results imply that the timing of viral administration and the immune status of the animals will be an important consideration in determining the effectiveness of viral therapies.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6076, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Miller
authors.forename: N W
authors.initials: NW
authors.lastname: Fraser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007276:Injections, Intraventricular; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D051379:Mice; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D022301:Herpes Simplex Virus Vaccines; D014613:Vaccines, Attenuated