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FP5

TARGETED GENE VECTOR Report Summary

Project ID: QLK3-CT-1999-00364
Funded under: FP5-LIFE QUALITY
Country: Spain

Validation of a targeted adenoviral vector expressing a therapeutic gene efficiently and safely in liver tumours in murine models

A set of targeted adenoviral vectors was evaluated for their efficient and safe therapeutic effects in murine liver tumour models.

HC-AdRS25 expresses mIL12 under RU486 inducible control. In an orthotropic liver tumour model, 1 x 10(6) MC-38 mouse colon cancer cells were injected into the left liver lobe of C57BL/6J syngenic mice. Seven days before implantation of tumour cells, mice received different doses of the RU486 inducible mIL12 HC-Ad vector (AdRS25) by intravenous injection. A single tumour nodule with a size of about 8 mm was observed in livers 5 days after inoculation of the tumour cells. At this time induction of IL-12 was initiated by i.p. injection of RU486. The treatment was continued by daily injection for a time of 10 days. Five days after completion of the induction regime, mice were sacrificed and tumour sizes were determined. Control animals that were treated with vector but that received no RU486 showed progressive tumour growth. In contrast, all animals that received 5 x 10(8) infectious units of AdRS25 and were induced with RU486 experienced complete tumour regression. Animals that were injected with a lower vector dose of 1 x 10(8) infectious units followed by RU486 induction showed a significant reduction of the tumour mass, but finally the disease progressed and the animals died as a consequence of massive liver metastases. This inducible vector is currently being adapted for clinical phase I trials.

HC-AdRS45 and HC-AdRS46 express sTie2 and sPEX. They were tested in orthotropic and subcutaneous tumour models of liver cancer in mice. Different from our expectations, there were only small tumour inhibitory effects.

AdRS44 and HC-AdRS23 expresses sFLT1 either constitutively (AdRS44, PEFBOS promoter) or in a RU486 inducible manner (AdRS23). After injection of the sFLT1 vectors very high levels of the expressed protein were observed in the serum. In the latter case there was no background expression in the absence of RU486 induction. Different from our expectations there were only small tumour inhibitory effects. After injection of the sFLT1 expressing vector significant side effects were observed; significant ascites, hypoalbuminemia and kidney damage. sFLT1 likely led to the kidney damage resulting in renal loss of serum albumin thereby causing hypoalbuminemia and ascites. These studies indicate that long-term inhibition of VEGF function will likely result in unacceptable side effects and may also have implications for studies that aim to inhibit VEGF by other than gene transfer strategies.

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