Die Applikation von Adeno-assoziierten Viren Typ 2 (AAV-2) führt zur Tumorprotektion in einem syngenen Rattenmodell des Pankreaskarzinoms

Abstract

AbstractThe success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. In this study we demonstrate that infection of Lewis rats bearing pancreatic tumors with the Adenoassociated Virus type 2 (AAV-2) induces a systemic anti-tumor response and protects these animals from a subsequent tumor rechallenge.AAV-2 is a small single stranded parvovirus with tumorsuppressive properties. DSL6A pancreatic tumor cells were inoculated subcutaneously and after 6 weeks AAV-2 infection with 108 virus particles was performed intratumorly (i. t.) or intra-peritoneally (i. p.) twice a week for 1 month. In this syngeneic tumor model the well established tumor (average size of 8 × 8 mm) was completely resected (Ro) 10 weeks after tumor cell inoculation. Six weeks later no local tumor recurrence was detected and tumor rechallenge experiment (106 DSL6A cells) on a different site was done.Within the next 8 weeks 11 of 12 (92%) untreated Lewis rats developed again a solid pancreatic tumor. In contrast, in case of TNF-α AAV-2-infected animals only 3 of 12 (25%) showed tumor growth. Analysis of cytokine profile demonstrated no significant changes of IL1β, IL4, IL6, INFγ and TNF-α, but the systemic cytokine level of IL10 and MCP-1 were significantly elevated in AAV-2 infected rats. 51Cr release assay revealed an enhanced anti-tumoral activity mostly provided by natural killer cells in AAV-2 infected animals. In line with these results further experiments showed that AAV-2 infection intratumorly was strongly associated with an enhanced infiltration of monocytes, macrophages, natural killer cells and CD8+ cytotoxic T lymphocytes.These results suggest that AAV-2 vaccination may stimulate the immune system and activate effector cells to protect Lewis rats against tumor cell challenge.