Type I IFN response and vector propagation
6 SUMMARY AND CONCLUSIONS
6 SUMMARY AND CONCLUSIONS
This work was carried out to study the utility of HSV-TK/GCV suicide gene therapy and oncolytic virotherapy against osteosarcoma, a highly aggressive primary bone tumor mainly affecting children and young adults.
I HSV-TK/GCV treatment was effective against human osteosarcoma cells. Both adenoviral and lentiviral vectors can be used for effective gene transfer to cultured osteosarcoma cells. However, the extent of the bystander effect varied between the studied cell lines, in two out of the three studied human osteosarcoma cell lines a strong bystander effect was observed whereas one cell line displayed a moderate bystander effect.
II Sindbis virus vectors have been reported to elicit effective gene transfer to multiple cell types. The chimeric split helper RNA has been developed for the production of Sindbis virus vectors as a way to reduce the possibility of wild-type reversion via recombination of replicon and helper RNAs. To our surprise, Sindbis vector preparations produced with split helper RNA contained propagation competent viruses or virus-like particles, giving rise to lateral spreading of transgene expression with no or minimal cytopathic effect that is normally associated with Sindbis virus propagation.
III Sindbis virus vectors produced with the split helper RNA can be used for gene transfer to human osteosarcoma cells, however, one of the three studied osteosarcoma cell lines was resistant to Sindbis virus vector mediated gene transfer. Nonetheless, recombination between the replicon and helper RNAs does occur and recombination events can lead to restoration of wild-type Sindbis sequences. Propagation competent Sindbis virus vectors may function like oncolytic viruses selectively killing malignant cells which have a defective IFN response.
IV Oncolytic Semliki Forest virus vector VA7-EGFP showed promising efficacy against osteosarcoma both in in vitro and in vivo against subcutaneous Saos2LM7 human
osteosarcoma tumors. In an orthotopic K7M3 mouse osteosarcoma model, weekly intratumoral VA7-EGFP injections significantly improved the survival of treated animals compared to controls. However, this study demonstrated that osteosarcoma cells may develop resistance against VA7-EGFP and serum IgM antibodies can neutralize the virus.
As a conclusion, the HSV-TK/GCV suicide gene therapy and oncolytic virotherapy with VA7-EGFP may represent novel tools for the treatment of unresectable osteosarcoma tumors or improving surgical margins after suboptimal resection. In the search for optimal vectors for therapeutic gene transfer, both adeno- and lentivirus vectors were shown to elicit efficient gene transfer to human osteosarcoma cells. Evaluation of one of the vector candidates, Sindbis virus vector, revealed the formation of propagation competent contaminating viruses or virus-like particles upon vector production. These had been generated due to recombination between the replicon and helper RNAs.
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