| The development of virus-based treatments for cancer requires an understanding of how the virus interacts with the entire organism. A previous report showed that a γ134.5 mutant HSV caused tumor regression in an immunocompetent murine model of retinoblastoma. In contrast to other studies, we discovered that viral replication and tumor destruction could not explain the antitumor effects of RE6. Another HSV-1 mutant hrR3, which was known to act oncolytically, also did not replicate in retinoblastoma cells or tissues. The work presented in this thesis showed evidence of an immune response that correlates with antitumor activity of the RE6 virus and which is absent in response to hrR3. We showed that the inflammatory immune mediators IFN-γ and TNF-α, which are known to be present after HSV-1 infection, have effects on human and mouse retinoblastoma cells. We have identified apoptosis as the primary antitumor effect of IFN- and TNF-α on cultured retinoblastoma cells. The results of gene analyses from cytokine treated retinoblastoma cells reveal potential pro-apoptosic and cell cycle-disruptive genes that might be added to future viral gene therapy treatments to augment antitumor effects in retinoblastoma. Future studies will focus on characterizing the immune response to the virus and design strategies to include genes that will make RE6 a more effective retinoblastoma therapy. |
