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Role of the Immune Response during Neuro-attenuated Herpes Simplex Virus-mediated Tumor Destruction in a Murine Intracranial Melanoma Model¹

Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Neuro-attenuated herpes simplex virus-1 (HSV-1) 34.5 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.

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