In vivo interleukin-2 gene therapy of established tumors with herpes simplex amplicon vectors

Abstract

In vivo cytokine gene transfer may greatly simplify autologous tumor vaccine production. Herpes simplex viral amplicon vectors (HSV) are efficient gene-transfer vehicles and may overcome many limitations of prior gene-transfer methods. The interleukin-2 (IL-2) and β-galactosidase genes (lac) were inserted into an HSV amplicon vector and tested in a subcutaneous squamous cell carcinoma of lung origin to determine the efficiency of in vivo gene transfer and the utility of such a direct gene-transfer approach in cancer therapy. Gene transfer and expression were assessed by histochemical staining and enzyme-linked immunosorbent assay (ELISA). Growth of injected tumors as well as non-injected tumors remote from the site of injection was assessed. Assessment of lymphocytic infiltrates into tumors was performed by immunohistochemistry. Survival was recorded. Direct in vivo injection of established tumors with a HSVil2 resulted in efficient gene transfer and production of IL-2 in the injected tumor but not at tumors remote from the sites of injection. There was a significant suppression of growth of the tumors injected with HSVil2 (P < 0.01) when compared with tumors injected with HSV without il2. Of note, growth of tumors remote from sites of HSVil2 injection was also retarded and treatment was associated with a significant (P < 0.05) improvement in survival. Direct intratumoral administration of HSV amplicon vectors can result in efficient transfer of cytokine genes and have antitumor efficacy. HSV vectors are therefore potentially useful agents in such in vivo gene-therapy strategies and simplify cytokine antitumor gene-therapy strategies.