Genetic engineering and preclinical evaluation of oncolytic herpes simplex viruses retargeted to cancer-specific receptors

摘要: Oncolytic virotherapy exploits the ability of viruses to infect and kill cells. It is suitable as treatment for tumors that are not accessible by surgery and/or respond poorly current therapeutic approach. HSV a promising oncolytic agent. has large genome size able accommodate transgenes some attenuated HSVs (oHSV) already in clinical trials phase I II. The aim this thesis was generation HSV-1 retargeted tumor-specific receptors detargeted from natural receptors, HVEM Nectin-1. retargeting achieved inserting specific single chain antibody (scFv) tumor receptor selected inside glycoprotein gD. In research three were considered: epidermal growth factor 2 (HER2) overexpressed 25-30% breast ovarian cancers gliomas, prostate membrane antigen (PSMA) expressed carcinomas neovascolature solid tumors; variant III (EGFRvIII). vivo studies on HER2 R-LM113 R-LM249 have demonstrated their high safety profile. For antitumor efficacy been highlighted target-specific inhibition human models HER2-positive cancer nude mice. murine model glioma mice, significantly increase survival time treated mice compared control. Up now, PSMA EGFRvIII (R-LM593 R-LM613) only characterized vitro, confirming targets. This strategy proved be generally applicable broad spectrum which available.