Construction And Research On The Oncolytic Activity Of A Novel Oncolytic Herpes Simplex Virus Type2

Oncolytic viruses are promising treatments for many kinds of solid tumors. Oncolytic virus can selectively infect tumor cells and kill tumor cells by direct cytopathic effect (oncolytic effect) and inducing immune responses by presenting tumor-associated antigen to DCs. Replication of oncolytic virus leads to the destruction of the infected tumor cells and release of progeny virions to infect adjacent tumor cells, which results in the further destruction of surrounding tumor cells. And oncolytic virus can be eliminated by anti-viral drugs (Aciclovir) to assure the safety of the oncolytic virus in the process of tumor treatment.In this study, we constructed a novel oncolytic herpes simplex virus type2:oHSV2. We investigated the cytopathic effects of oHSV2in vitro and tested its antitumor effects in4T1breast cancer mouse model. We compared its effect on the cell cycle and its immunologic impact with the traditional chemotherapeutic agent doxorubicin.In vitro data showed that oHSV2infected most of the human and mouse tumor cell lines and was highly oncolytic. oHSV2infected and killed4T1tumor cells independent with their cell cycle phase, however doxorubicin mainly exhibit blocking effects in S and G2/M phase. In vivo study showed that both oHSV2and doxorubicin had an antitumor effect, and oHSV2was less toxic and safer. oHSV2treatment alone not only slowed down the growth of tumors without causing weight loss but also induced an elevation of NK cells and decrease of Tregs in spleen. In addition, combination therapy of doxorubicin followed by oHSV2achieved increased animal survival than oHSV2alone.Therefore, we concluded that our virus is a safe and effective therapeutic agent for4T1breast cancer and that the sequential use of doxorubicin followed by oHSV2could improve antitumor activity without enhancing doxorubicin’s toxicity.