Factors That Limit the Effectiveness of Herpes Simplex Virus Type 1 for Treatment of Oral Cancer in Mice

Abstract

Although the growth of experimental oral cancers can be inhibited by infection with the herpes simplex virus type 1 (HSV-1), the effect is incomplete. To define factors that might limit the effectiveness of the virus, we examined the roles of the innate immune system and the replication status of the tumor cells. AT-84 tumors were induced in strains of mice that had specific immune defects and were treated with the virus. Explanted tumors and tumor cells in culture were also infected. No differences in viral replication or in the effect of virus on the tumor were seen between mice with a lack of Tor B lymphocytes, natural killer cells, phagocytic spleen cells, or complement. The virus did not replicate significantly more in tumors that were maintained as explants. Immediately after recovery of cells from a tumor the proportion of cells in the S phase was around 18%, and replication of virus in those cells was very limited. After 3 weeks in culture, the proportion in S had increased to 50% and both the recovery of virus from the cells and the toxic effect of the virus on the cells had increased significantly. The innate immune system thus seemed to have a minimal effect on replication of HSV-1when used as an oncolytic virus for oral cancers in mice. Instead, the fraction of cells in the S phase was important. Because human oral cancers, like mouse tumors, have a low fraction of cells in the S phase, it is likely that the in vivo use of HSV-1as cancer therapy will be limited by the replication of the virus.Several recent studies have evaluated the potential of replication-competent strains of herpes simplex virus type 1 (HSV-1) for therapy of cancer. Because the virus is able to multiply within tumor cells, it could be expected to proliferate throughout a tumor, thus eliminating it (1). One tumor type that might benefit from this is squamous cell cancer of the mouth, which arises from the mucous membrane that is the natural host for HSV-1. However, despite the attractiveness of oncolytic viral therapy for oral cancer, the results have yet to match the expectations. In a previous study with the AT-84 mouse model, we found that wild-type HSV-1 was rapidly eliminated from the tumors, and although the growth of the tumor was reduced while the virus was present, it resumed after the virus was lost (2). The injection of a second dose of virus gave greater inhibition of the tumor, which is consistent with the idea that the concentration of virus in the tumor is an important determinant of its antitumor effect. We thus concluded that replication of the virus within the tumor was essential for the optimal antitumor effect and that the limited results to date can be attributed to failure of the virus to multiply effectively.One possible explanation for failure of HSV-1 to replicate in tumors would be the effects of the immune response, either innate or acquired. In a rodent model of glioblastoma multiforme, it has been shown that replication of HSV-1 is inhibited by the animals' immunity. Complement and natural ant...

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