Role of the immune response during neuro-attenuated herpes simplex virus-mediated tumor destruction in a murine intracranial melanoma model

Neuro-attenuated herpes simplex virus-1 (HSV-1) gamma 34.5 mutants can slow progression of preformed tumors and lead to complete regression of some tu mors. However, the role of the immune response in this process is poorly un derstood. Syngenic DBA/2 tumor-bearing mice treated with HSV-1 1716 fourtee n days after tumor implantation had significant prolongation in survival wh en compared with mice treated with viral growth sera (mock; 38.9 +/- 2.3 ve rsus 24.9 +/- 0.6, respectively; P < 0.0001), Additionally, 60% of the anim als treated on day 7 had complete regression of the tumors. However, no dif ference was observed in the mean survival rates of viral- or mock-treated t umor-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 cyclophos phamide 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 immun e response contributes to the viral-mediated tumor destruction and the incr ease in survival. Immune cell infiltration was up-regulated, specifically C D4+ T cells and macrophages (which are found early after viral administrati on). Prior immunity to HSV-I increased survival times of treated mice over those of naive mice, an important consideration because 50-95% of the adult human population is sere-positive for HSV-1. Our results imply that the ti ming of viral administration and the immune status of the animals will be a n important consideration in determining the effectiveness of viral therapi es.